T3P-promoted synthesis of a series of novel 3-aryl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones

Article abstract of DOI:10.1002/jhet.3904

A series of 11 novel 3-aryl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-aryl-C-phenyl imines with thiosalicylic acid. This provides simple and ready access to N-aryl compounds in this family, which have been generally difficult to prepare.

Full text of DOI:10.1002/jhet.3904

Received: 14 November 2019
DOI: 10.1002/jhet.3904
Revised: 12 December 2019
Accepted: 2 January 2020
A R T I C L E
T3P-promoted synthesis of a series of novel 3-aryl-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-4-ones
Lee J. Silverberg1
Hany F. Sobhi4
| Carlos Pacheco2
| Debashish Sahu2 | Peter Scholl3
|
| Joshua T. Bachert1 | Kaitlyn Bandholz1
|
Ryan V. Bendinsky1 | Heather G. Bradley1 | Baylee K. Colburn1
David J. Coyle1 | Jonathon R. Dahl1 | Megan Felty1 | Ryan F. Fox1
Kyanna M. Gonzalez1 | Jasra M. Islam1 | Stacy E. Koperna1
|
|
|
Quentin J. Moyer1 | Duncan J. Noble1 | Melissa E. Ramirez1 | Ziwei Yang1
1Department of Chemistry, Pennsylvania State University, Schuylkill Haven, Pennsylvania
2Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania
3Spectroscopy and Mass Spectrometry Branch, Food and Drug Administration, College Park, Maryland
4Department of Chemistry, Science and Technology Center, Coppin State University, Baltimore, Maryland
Correspondence
Lee J. Silverberg, Pennsylvania State
Abstract
University, Schuylkill Campus,
200 University Drive, Schuylkill Haven,
PA 17972.
A series of 11 novel 3-aryl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones was
prepared at room temperature by T3P-mediated cyclization of N-aryl-C-phenyl
imines with thiosalicylic acid. This provides simple and ready access to N-aryl
compounds in this family, which have been generally difficult to prepare.
Email: ljs43@psu.edu
Funding information
SP Controls, Inc.; Pennsylvania State
University Schuylkill Campus
1 | INTRODUCTION
1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P),[17]
which has become a commonly used reagent for peptide
The 2,3-dihydro-4H-1,3-benzothiazin-4-ones (Figure 1) are
a class of compounds that have demonstrated a variety of
types of bioactivity.[1–10] This may be a function of both
the 1,3-thiazin-4-one ring[11] and the fused benzene.[12]
An assortment of methods have been reported for the
preparation of 2,3-dihydro-4H-1,3-benzothiazin-4-ones.[11]
The most frequently used method is the condensation of
thiosalicylic acid with an imine.[11] However, the lesser
nucleophilicity of the N-aryl imines makes it more difficult
to prepare the N-aryl compounds than N-H or N-alkyl ana-
logs. For example, Loev reported that in refluxing benzene,
2-(4-chlorophenyl)-3-methyl-4H-1,3-benzothiazin-4-one
could be prepared, but the 3-phenyl product could not.[13]
As detailed previously,[14–16] our initial attempts at the
synthesis of 2,3-diphenyl-2,3-dihydro-4H-1,3-benzothiazin-
4-one (1i) were unsuccessful. We turned to 2,4,6-tripropyl-
coupling between an amine and a carboxylic acid as well
as other reactions.[18] T3P has several advantages
over other amide-forming reagents, including that the
byproducts are water soluble and easily removed, the
reagent is safe, and in combination with pyridine
epimerization at the carbon alpha to the carboxylic acid is
minimized.[19] We have demonstrated that 1i and other N-
aryl-2,3-dihydro-4H-1,3-benzothiazin-4-ones can be suc-
cessfully prepared using T3P and pyridine at room temper-
ature (RT),[14–16,20–23] including the preparation of a series
of 2-aryl-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones,
where substituents were varied on the aryl ring which is
attached to the 2-position of the heterocycle.[16] Kitsiou
et al[24] and Unsworth et al[25] have reported similar chem-
istry for the reaction of imines with thiosalicylic acid (T3P,
DIPEA, 90ꢀC), but only one example had an N-aryl group,
J Heterocyclic Chem. 2020;1–9.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
SILVERBERG ET AL.
and the yield was notably lower than the N-alkyl examples
(53%, compared with 99% for a similar N-alkyl), which
again shows the difficulty of N-aryls.[24]
Herein, we report the further exploration of the scope
of this reaction by preparing a series of 3-aryl-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-4-ones in which various
substituents are on the aryl ring which is attached to the
3-position (the nitrogen) of the heterocycle.
meta and para positions. Yields of recrystallized com-
pounds 1b-m were modest, ranging from 17% to 43% and
averaging 31% (Table 1) but are similar to those observed
in the 2-aryl-3-phenyl series (12%-43%, average 29%).[16]
The one example of an N-aryl compound prepared by
Kitsiou et al was done using 1.2 equivalents thiosalicylic
acid, and the product was not recrystallized.[24] The lowest
yield was of compound 1j, which gave a good yield of
product from chromatography, but whose recrystallization
proved difficult, and ultimately a poor recovery was real-
ized. The low yields in general are a function of the two
substrates. We have seen that reactions using
3-mercaptopropionic acid are much faster and higher
yielding than thiosalicylic acid,[27–29] presumably because
the aromatic thiol is less nucleophilic. As discussed earlier,
the N-aryl group on the imine makes the reaction slower
and lower yielding than an N-alkyl.
Compound 1a (para-nitro) did not form, even when
the reaction was refluxed. It was attempted both with
imine 2a and as a three-component coupling. This was
the first instance in our experience when the reaction did
not work. The meta-nitro compound 1b did form, and all
other substituents worked for both meta and para. This
suggests that the strongly electron-withdrawing nitro
group, when in the para position, renders the imine
nitrogen too electron-poor to attack the presumed phos-
phate intermediate (vide infra).[14,25] In the meta posi-
tion, the nitro group is less able to exert this effect.
2 | RESULTS AND DISCUSSION
The imines 2a-h and 2k-m for this investigation, which are
all known compounds, were prepared by refluxing anilines
3a-h and 3j-m with benzaldehyde 4 in toluene while cap-
turing water with a Dean-Stark trap (Scheme 1).[16,26]
The imines were recrystallized, except for three cases
where the imine was a liquid (2h, 2k, and 2m) and one
where the solid was not recrystallized (2f), in which cases
the imines were used as is. 3-Methoxyaniline (3m) was
received as a brown liquid and vacuum distilled twice to
give a colorless liquid, which was used to prepare the imine
2m as a yellow liquid. This step made purification of com-
pound 1m much easier. Compound 1j was prepared by a
three-component reaction, forming the imine 2j in situ.
The condensation of 1 equivalent thiosalicylic acid 5
with 1 equivalent imines 2a-h and 2j-m was performed in
the same manner as previously reported,[14–16,20–23] using
T3P as
a
promoter and pyridine as
a
base in
Unsworth et al have studied the mechanism of the
related reaction using an N-alkylimine and 5-nitro-
salicylic acid (─OH instead of ─SH) and proposed a
mechanism in which the acid is first activated by reaction
with T3P, then the imine nitrogen attacks the activated
carbonyl, leaving an iminium ion that is attacked at C2
by the oxygen.[25] In our reactions of N-aryl imines with
thiosalicylic acid, we have not observed anything that
would argue against this same type of mechanism. It is
also possible that the initial step is attack of the sulfur at
the imine carbon, but reaction of thiosalicylic acid with
N-benzylideneaniline 2i in 2-methyltetrahydrofuran at
RT without T3P/pyridine did not occur, so this is
unlikely. A possible pathway is thus shown in Scheme 2.
2-methyltetrahydrofuran at RT (Scheme 1). The reaction is
operationally simple and does not require dry solvents. A
variety of electron-withdrawing and electron-donating
substituents on the 3-aryl ring were used in both the
O
3
N
R2
4
S
1
R1
2
FIGURE 1 2,3-Dihydro-4H-1,3-benzothiazin-4-one skeleton
(R1 = H, alkyl, aryl, heteroaryl, R2 = H, alkyl, aryl, heteroaryl)
SCHEME 1 Preparation of 3-aryl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones 1a-m

SILVERBERG ET AL.
3
TABLE 1 Reaction of imines 2a-m with thiosalicylic acid 5
X-ray crystallographic structures of compounds 1c, 1f,
and 1l have been previously reported.[22] Full spectral
data and physical properties are provided in the Section 4
and 1H, 13C, and 19F NMR and IR spectra are provided in
the Supporting Information.
Compound
R
Yield
0
1a
p-NO2
m-NO2
p-CF3
m-CF3
p-Br
1b
1c[22]
29%a
24%b
24%c
1d
29%c
3 | CONCLUSIONS
1e
1f[22]
m-Br
p-F
28%c,d
43%e
A
series of novel 3-aryl-2-phenyl-2,3-dihydro-4H-
1g
1,3-benzothiazin-4-ones has been synthesized in modest
yields from N-aryl-C-phenyl imines using the T3P/pyridine
method.[14–16,20–23] The para-nitro compound 1a did not
form, presumably because the imine nitrogen was not
nucleophilic enough. Combined with our prior results using
C-aryl-N-phenyl imines,[16] it has been demonstrated that a
wide range of 2,3-diaryl-2,3-dihydro-4H-1,3-benzothiazin-
4-ones can be readily accessed by this chemistry.
1h
1i[14–16]
m-F
26%b,f
35%[16]
17%b,g
42%b,f
35%b
36%b,f,h
H
1j
p-Me
m-Me
p-OMe
m-OMe
1k
1l[22]
1m
Note: 1.0 eq. thiosalicylic acid, 1.0 eq. imine, 4.0 eq. pyridine, 2.0 eq. T3P,
2-methyltetrahydrofuran, room temperature.
aYield after chromatography and two recrystallizations.
bYield after chromatography and recrystallization.
cYield after chromatography, trituration, and recrystallization.
dThe imine was used as a crude solid.
eYield after recrystallization.
fThe imine was used as a crude liquid.
gThree-component coupling (imine prepared in situ).
hThe amine used to make the imine was vacuum distilled twice
before use.
4 | EXPERIMENTAL SECTION
4.1 | General
Toluene,
acid, benzaldehyde, 3-bromoaniline, 4-bromoaniline,
3-fluoroaniline, 4-fluoroaniline, 3-nitroaniline,
2-methyltetrahydrofuran,
thiosalicylic
SCHEME 2 Possible pathway of the cyclization reaction

4
SILVERBERG ET AL.
4-nitroaniline, 4-methoxyaniline, 3-(trifluoromethyl)
aniline, and silica gel for flash chromatography
(cat. no. 60737) were purchased from Sigma-Aldrich.
distilled into the trap until water was no longer being
produced, generally 30 minutes or less. After cooling,
the toluene was removed under vacuum if the imine
did not crystallize directly from the reaction mixture.
The product was recrystallized from an appropriate
solvent or used crude. Recrystallization solvents,
yields, and melting points (where appropriate) are
reported below.
4-Methylaniline
was
purchased
from
JTBaker.
3-Methylaniline, 3-methoxyaniline, N-benzylideneaniline
and pyridine were purchased from AlfaAesar. Commercial
3-methoxyaniline was vacuum distilled twice before use.
4-(Trifluoromethyl)aniline was purchased from May-
bridge. T3P in 2-methyltetrahydrofuran (50 wt%) was
obtained from Euticals, Inc. TLC plates (silica gel GF,
250 μm, 10 × 20 cm, cat. no. 21521) were purchased from
Analtech. TLCs 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 Thermo-Fisher NICOLET iS50 FT-IR using a
diamond-ATR attachment for the direct powder analysis
4.2.1 | 4-Nitro-N-[phenylmethylidene]
aniline (2a)
Recrystallized directly from the reaction mixture to give
yellow crystals (8.44 g, 76%). mp: 109ꢀC-113ꢀC (lit.
117ꢀC-119ꢀC[30]).
1
(Coppin State University). H, 13C, and 19F NMR experi-
ments (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. Samples
were dissolved in CDCl3 and analyzed at RT. Typical con-
ditions for 1H acquisition were 1-second relaxation delay,
acquisition time of 2.76 seconds, spectral width of
12 kHz, and 16 scans. Spectra were zero-filled to 128k
points, and multiplied by exponential multiplication
(EM with LB = 0.3 Hz) prior to FT. For 13C experiments
a 2-second relaxation delay was employed, with acquisi-
tion time of 0.9088 second, spectral width of 36 kHz, and
128 scans. Spectra were zero-filled once and multiplied
by EM with LB = 2 Hz prior to FT. For 19F experiments,
a 3-second relaxation delay was employed, with an acqui-
sition time of 0.5767 second, spectral width of 113.6 kHz,
and 32 scans. Spectra were zero-filled once and multi-
plied by EM with LB = 1 Hz prior to FT. High-resolution
mass spectra were acquired under positive ESI conditions
at a resolution of 120 000 using a Thermo Scientific Q
Exactive HF mass spectrometer (FDA). 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).
4.2.2 | 3-Nitro-N-[phenylmethylidene]
aniline (2b)
Recrystallized from ethanol to give pale yellow powder
(9.50 g, 84%). mp: 68.5ꢀC-70ꢀC (lit. 66ꢀC-68ꢀC[31]).
4.2.3 | N-[Phenylmethylidene]-
4-(trifluoromethyl)aniline (2c)
Recrystallized from hexanes to give pale yellow powder
(10.38 g, 84%). mp: 63ꢀC-64ꢀC (lit. 65ꢀC[32]).
4.2.4 | N-[Phenylmethylidene]-
3-(trifluoromethyl)aniline (2d)
Recrystallized from toluene/hexanes to give white
crystals (9.96 g, 80%). mp: 64ꢀC-66ꢀC (lit. 66ꢀC-
67ꢀC[32]).
4.2.5 | 4-Bromo-N-[phenylmethylidene]
aniline (2e)
Recrystallized from hexanes to give light yellow crystals
(11.07 g, 85%). mp: 64ꢀC-66ꢀC (lit. 66ꢀC-68ꢀC[33]).
4.2 | General procedure for preparation
of imines 2b-h and 2k-m
A 100-mL round-bottom flask with a stir bar was
charged with benzaldehyde (0.05 mol), a substituted
aniline (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
4.2.6 | 3-Bromo-N-[phenylmethylidene]
aniline (2f)
Used as crude off-white solid (12.62 g, 97%). mp: 49ꢀC-
52ꢀC (mp not give in lit.[34]).

SILVERBERG ET AL.
5
4.2.7 | 4-Fluoro-N-[phenylmethylidene]
aniline (2g)
sodium chloride (10 mL). The organic 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.
Recrystallized from ethanol to yield pale yellow solid
(6.88 g, 69%). mp: 52ꢀC-54ꢀC (lit. 57.8ꢀC-58.2ꢀC[35]).
4.3.1 | 3-(3-Nitrophenyl)-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-4-one (1b)
4.2.8 | 3-Fluoro-N-[phenylmethylidene]
aniline (2h)
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, recrystallization from
2-propanol produced pale yellow solid (0.7415 g, slightly
impure by TLC and NMR). A second crop gave 0.027 g, a
total of 0.7685 g. Recrystallization of 0.6914 g of the com-
bined solids from dichloromethane/methanol gave pale yel-
low solid (0.5025 g, 72.7% recovery, overall 26% yield). mp:
168ꢀC-170ꢀC. A second crop of 0.0708 g was isolated (total
Used as crude brown liquid (9.31 g, 93%) (mp not given
in lit.[36]).
4.2.9 | 3-Methyl-N-[phenylmethylidene]
aniline (2k)
1
Used as crude brown liquid (7.14 g, 72%) (lit. mp
41ꢀC[37]).
yield 0.5733 g, 29%). H NMR (CDCl3): δ (ppm): 8.23 (2H,
m, Ar connected to C5), 8.14 (1H, d, 3JHH 8.5 Hz), 7.68 (1H,
3
3
d, JHH 7.3 Hz), 7.55 (1H, m), 7.43 (2H, d, JHH 7.3 Hz),
3
7.39 (1H, d, JHH 7.3 Hz), 7.39-7.28 (4H, m), 7.22 (1H, d,
4.2.10 | 4-Methoxy-N-
[phenylmethylidene]aniline (2l)
3JHH 7.3 Hz), 6.14 (s, 1H, C2). 13C NMR (CDCl3): δ (ppm):
163.9 (C═O), 148.6, 143.1, 136.3, 133.4, 133.0, 132.0, 130.6,
129.8, 128.8, 127.8, 126.9, 126.6, 121.8, 121.3, 65.2 (C2).
HRMS (m/z): [M + H]+ of 363.0795 is consistent with cal-
culated [M + H]+ of 363.0795. IR (neat, cm−1): 1658.5
(C═O). UV/Vis (CH3CN): λmax: 283 nm (shoulder at
approximately 319 nm). Rf (40% EtOAc/hexanes) = 0.52.
Previously reported.[26]
4.2.11 | 3-Methoxy-N-
[phenylmethylidene]aniline (2m)
3-Methoxyaniline was vacuum distilled twice to give a
colorless liquid. This was used to produce the imine as a
yellow liquid (8.95 g, 85%) (mp not given in lit.[38]).
4.3.2 | 2-Phenyl-3-[4-(trifluoromethyl)
phenyl]-2,3-dihydro-4H-1,3 benzothiazin-
4-one (1c)[22]
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, recrystallization from dic-
hloromethane/hexanes gave yellow solid (0.5639 g, 24%
4.3 | General procedure for preparation
of 3-aryl-2-phenyl-2,3-dihydro-4H-
1,3-benzothiazin-4-ones 1a-h and 1k-m
1
yield). mp: 131ꢀC-133ꢀC. H NMR (CDCl3): δ (ppm): 8.23
3
(1H, d, JHH 8.5 Hz, Ar connected to C5), 7.64 (2H, dq,
4
3
A two-necked 25-mL round-bottom flask was oven-dried,
cooled under N2, and charged with a stir bar and an
imine (6 mmol) and thiosalicylic acid (0.931 g, 6 mmol).
Tetrahydrofuran or 2-methyltetrahydrofuran (2.3 mL)
was added and the solution was stirred. Pyridine
(1.95 mL, 24 mmol) was added, and then finally, T3P in
2-methyltetrahydrofuran (50 wt%; 7.3 mL, 12 mmol) was
added. The reaction was stirred at RT (usually at least
overnight) and followed by TLC, then poured into a
separatory funnel with dichloromethane (20 mL). The
mixture was washed with water (10 mL). The aqueous
was then extracted twice with dichloromethane (10 mL
each). The organics were combined and washed with sat-
urated sodium bicarbonate (10 mL) and then saturated
3JHH 8.5, JHF 0.7 Hz, Ar ortho to CF3), 7.48 (2H, dq, JHH
8.5, 5JHF 0.7 Hz, Ar meta to CF3), 7.43 (2H, d, 3JHH 6.1 Hz),
3
7.37 (1H, m), 7.30 (4H, m), 7.20 (1H, d, JHH 8.5 Hz), 6.09
(1H, s, C2). 13C NMR (CDCl3): δ (ppm): 163.8 (C═O),
145.4, 138.9, 133.2, 132.8, 130.6, 129.3, 129.0, 128.7, and
2
128.5 (q, JCF 32.7 Hz, Ar connected to CF3), 129.1, 128.7,
3
128.6, 128.6, 128.5, 127.8, 126.55, and 126.52 (d, JCF
3
3.6 Hz, Ar ortho to CF3); 126.34-126.26 (q, JCF 3.6 Hz, Ar
ortho to CF3), 127.1 and 124.9 and 122.7 and 120.6 (q, 1JCF
272 Hz, CF3), 65.1 (C2). 19F NMR (CDCl3): δ(ppm): −62.54
(s, CF3). HRMS (m/z): [M + H]+ of 386.08164 is consistent
with calculated [M + H]+ of 386.0821. IR (neat, cm−1):
1641.6 (C═O). UV/Vis (CH3CN): λmax: 280 nm (shoulder at
approximately 319 nm). Rf (30% EtOAc/hexanes) = 0.58.

6
SILVERBERG ET AL.
4.3.3 | 2-Phenyl-3-[3-(trifluoromethyl)
phenyl]-2,3-dihydro-4H-1,3-benzothiazin-
4-one (1d)
solid. Recrystallization from toluene/hexanes gave white
solid in two crops (total 0.6601 g, 28% yield). mp first
1
crop: 123ꢀC-125ꢀC. H NMR (CDCl3): δ (ppm): 8.22 (1H,
3
d, JHH 7.6 Hz, Ar connected to C5), 7.55 (1H, s), 7.42
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, trituration with hexanes gave
a solid. Recrystallization from ligroin (90ꢀC-110ꢀC boiling
range) gave off-white solid (0.5574 g, 24% yield). mp:
(3H, d, 3JHH 6.1 Hz), 7.36 (1H, m), 7.27 (7H, m), 7.19 (2H,
3
d, JHH 6.7 Hz), 6.05 (1H, s, C2). 13C NMR (CDCl3): δ
(ppm): 163.8 (C═O), 143.5, 138.9, 137.9, 133.3, 132.7,
130.5, 130.4, 130.3, 129.3, 129.2, 129.1, 128.6, 128.5, 128.3,
126.6, 126.5, 125.3, 124.5, 122.5, 65.2 (C2). HRMS (m/z):
[M + H]+ of 396.00467 is consistent with calculated [M
+ H]+ of 396.00522. IR (neat, cm−1): 1635.3 (C═O).
UV/Vis (CH3CN): λmax: 280 nm (shoulder at approxi-
mately 319 nm). Rf (20% EtOAc/hexanes) = 0.51.
1
113ꢀC-117ꢀC. H NMR (CDCl3): δ (ppm): 8.23 (1H, d,
3JHH 7.3 Hz, Ar connected to C5), 7.64 (1H, s, Ar ortho to
3
CF3, ortho to N), 7.52 (3H, m), 7.43 (2H, d, JHH 6.7 Hz),
3
7.38 (1H, t, JHH 7.3 Hz, Ar meta to CF3), 7.30 (4H, d,
3
3JHH 7.0 Hz), 7.21 (1H, d, JHH 7.3 Hz, Ar ortho to CF3,
para to N), 6.09 (1H, s, C2). 13C NMR (CDCl3): δ (ppm):
163.9 (C═O), 142.7, 138.7, 133.4, 132.8, 132.0-131.2 (q,
2JCF 32.7 Hz, Ar connected to CF3), 130.5, 129.7, 129.2,
129.1, 128.7, 128.6, 127.8, 126.58, 126.55, 126.8, 124.7,
4.3.6 | 3-(4-Fluorophenyl)-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-4-one (1g)
1
122.5, and 120.4 (q, JCF 272 Hz, CF3), 123.87-123.79 (q,
3
3JCF 3.6 Hz, Ar ortho to CF3), 123.19-123.09 (q, JCF 3.6,
Recrystallization from toluene gave white solid (0.8556 g,
Ar ortho to CF3), 65.2 (C2). 19F NMR (CDCl3): δ (ppm):
−62.66 (s, CF3). HRMS (m/z): [M + H]+ of 386.08161 is
consistent with calculated [M + H]+ of 386.0821. IR
43% yield). mp: 167ꢀC-170ꢀC. 1H NMR (CDCl3): δ (ppm):
3
4
8.23 (1H, dd, JHH 7.9, JHH 1.6 Hz, Ar connected to C5),
3
7.43-7.39 (2H, m, Ar meta to F), 7.36 (1H, td, JHH 7.5,
(neat, cm−1): 1659.8 (C═O). UV/Vis (CH3CN): λmax
:
4JHH 1.6 Hz,), 7.33-7.23 (6H, m,), 7.19 (1H, dd, JHH 7.8,
3
277 nm (shoulder at approximately 316 nm). Rf (30%
EtOAc/hexanes) = 0.57.
4JHH 1.3 Hz,), 7.10-7.03 (2H, m, Ar ortho to F), 6.01 (1H,
s, C2). 13C NMR (CDCl3): δ (ppm): 164.0 (C═O), 162.1
1
and 160.5 (d, JCF 246.5 Hz, Ar-F), 139.1, 138.34, and
5
138.32 (d, JCF 3.3 Hz, Ar para to F), 133.3, 132.5, 130.4,
3
4.3.4 | 3-(4-Bromophenyl)-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-4-one (1e)
129.3, 129.1, 128.6, 128.4, 127.94, and 127.89 (d, JCF
7.7 Hz, Ar meta to F), 127.7, 126.6, 126.4, 116.1, and 116.0
2
(d, JCF 22.0 Hz, Ar ortho to F), 65.3 (C2). 19F NMR
3
4
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, recrystallization from
2-propanol gave bright yellow powder (0.6802 g, 29%
yield). mp: 116ꢀC-118ꢀC. 1H NMR (CDCl3): δ (ppm): 8.22
(CDCl3): δ (ppm): −114.17 (tt, JHF 8.2, JHF 4.8 Hz).
HRMS (m/z): [M + H]+ of 336.08679 is consistent with
calculated [M + H]+ of 336.08529. IR (neat, cm−1):
1648.9 (C═O). UV/Vis (CH3CN): λmax
:
280 nm
3
(1H, d, JHH 6.7 Hz, Ar connected to C5), 7.49 (2H, d,
(shoulder at approximately 316 nm). Rf (15% EtOAc/
hexanes) = 0.32.
3JHH 8.5 Hz), 7.40 (2H, d, 3JHH 6.4 Hz), 7.35 (1H, m), 7.28
3
3
(4H, d, JHH 7.0 Hz), 7.22 (2H, d, JHH 8.5 Hz), 7.19 (1H,
d, JHH 7.6 Hz), 6.02 (1H, s, C2). 13C NMR (CDCl3): δ
3
(ppm): 163.8 (C═O). 141.4, 139.0, 133.3, 132.6, 132.3,
130.5, 129.2, 128.6, 128.5, 127.7, 127.6, 126.54, 126.49,
120.6, 65.2 (C2). HRMS (m/z): [M + H]+ of 396.00489 is
consistent with calculated [M + H]+ of 396.00522. IR
4.3.7 | 3-(3-Fluorophenyl)-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-4-one (1h)
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, recrystallization from ethanol/
water produced yellow solid (0.5291 g, 26% yield). mp:
(neat, cm−1): 1646.7 (C═O). UV/Vis (CH3CN): λmax
:
274 nm (shoulder at approximately 319 nm). Rf (20%
EtOAc/hexanes) = 0.55.
1
3
88ꢀC-91ꢀC. H NMR (CDCl3): δ (ppm): 8.23 (1H, d, JHH
3
7.6 Hz, Ar connected to C5), 7.42 (2H, d, JHH 7.7 Hz),
3
7.37-7.26 (7H, m), 7.20 (1H, d, JHH 7.7 Hz), 7.12 (2H,
4.3.5 | 3-(3-Bromophenyl)-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-
4-one (1f)[22]
dtd, 3JHF 9.5, 4JHH 2.2, 5JHH 1.0 Hz, Ar ortho to F, ortho to
3
3
4
N), 7.00 (1H, td, JHH ≈ JHF 8.5, JHH 1.0 Hz, Ar ortho
to F, para to N), 3JHH 6.06 (1H, s, C2). 13C NMR (CDCl3):
1
δ (ppm): 163.74 (C═O), 163.55 and 161.9 (d, JCF
3
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, trituration from hexanes gave
247.6 Hz, Ar-F); 143.73 and 143.66 (d, JCF 9.9 Hz, Ar
meta to F), 139.0, 133.2, 132.6, 130.5, 130.29 and 130.22

SILVERBERG ET AL.
7
3
(d, JCF 8.8 Hz, Ar meta to F), 129.3, 128.6, 128.5, 127.7,
(CH3CN): λmax: 274 nm (shoulder at approximately
310 nm). Rf (50% EtOAc/hexanes) = 0.53.
126.54, 126.49, 121.41 and 121.39 (d, 4JCF 3.3 Hz, Ar para
to F), 114.23 and 114.09 (d, JCF 21.5 Hz, Ar ortho to F),
2
2
113.63 and 113.47 (d, JCF 24.2 Hz, Ar ortho to F), 65.2
(C2). 19F NMR (CDCl3): δ (ppm): −111.29 (m). HRMS
(m/z): [M + H]+ of 336.08682 is consistent with calcu-
lated [M + H]+ of 336.08529. IR (neat, cm−1): 1651.
(C═O). UV/Vis (CH3CN): λmax: 283 nm (shoulder at
approximately 316 nm). Rf (30% EtOAc/hexanes) = 0.50.
4.3.11 | 3-(3-Methoxyphenyl)-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-4-one (1m)
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, 1.193 g of material that was
solid at −10ꢀC but oil at RT was obtained. Recrystalliza-
tion of 1.0902 g from ethyl acetate/hexanes gave white
crystals (0.6192 g, 57% recovery, 36% yield). mp: 84ꢀC-
4.3.8 | 2,3-Diphenyl-2,3-dihydro-4H-
1,3-benzothiazin-4-one (1i)
1
3
86ꢀC. H NMR (CDCl3): δ (ppm): 8.23 (1H, dd, JHH 7.8,
3
1.3 Hz, Ar connected to C5), 7.43 (2H, d, JHH 7.4 Hz,),
7.34 (1H, td, JHH 7.6, 1.5 Hz), 7.31-7.20 (6H, m), 7.18
Previously reported.[14,16]
3
(1H, d, 3JHH 7.7 Hz), 6.96-6.87 (2H, m), 6.84 (1H, dd, 3JHH
8.3, 2.4 Hz,), 6.05 (1H, s, C2), 3.78 (3H, s, OCH3). 13C
NMR (CDCl3): δ (ppm): 163.8 (C═O), 160.1, 143.6, 139.4,
133.3, 132.4, 130.4, 129.9, 129.5, 128.5, 128.3, 127.7, 126.6,
126.4, 118.0, 113.0, 112.0, 65.3 (C2), 55.4 (OCH3). HRMS
(m/z): [M + H]+ of 348.10487 is consistent with calcu-
lated [M + H]+ of 348.10528. IR (neat, cm−1): 1647.0
(C═O). UV/Vis (CH3CN): λmax: 280 nm (shoulder at
approximately 322 nm). Rf (30% EtOAc/hexanes) = 0.27.
4.3.9 | 3-(3-Methylphenyl)-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-4-one (1k)
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, recrystallization from
2-propanol gave off-white solid (0.8376 g, 42% yield). mp:
1
106ꢀC-110ꢀC. H NMR (CDCl3): δ (ppm): 8.23 (1H, d,
3
3JHH 7.9 Hz, Ar connected to C5), 7.44 (2H, d, JHH
7.3 Hz), 7.35-7.21 (7H, m), 7.18 (1H, d, 3JHH 7.9 Hz), 7.11
3
(2H, t, JHH 6.7 Hz), 6.04 (1H, s, C2), 2.35 (3H, s, CH3).
4.3.12 | Three-component preparation of
3-(4-methylphenyl)-2-phenyl-2,3-dihydro-
4H-1,3-benzothiazin-4-one (1j)
13C NMR (CDCl3): δ (ppm): 163.8 (C═O), 142.5, 139.6,
139.2, 133.3, 132.4, 130.4, 129.6, 129.1, 128.4, 128.2, 128.1,
127.7, 126.8, 126.6, 126.4, 122.8, 65.3 (C2), 21.4 (CH3).
HRMS (m/z): [M + H]+ of 332.10995 is consistent with
calculated [M + H]+ of 332.11036. IR (neat, cm−1):
A two-necked 25-mL round-bottom flask was oven-dried,
cooled under N2, and charged with a stir bar. Benzalde-
hyde (0.637 g, 6 mmol) and p-toluidine (0.643 g, 6 mmol)
were added. 2-Methyltetrahydrofuran (2.3 mL) was added
and the solution was stirred for 5 minutes. Thiosalicylic
acid (0.931 g, 6 mmol) and pyridine (2.9 mL, 36 mmol)
were added. Finally, T3P in 2-methyltetrahydrofuran
(50 wt%; 11.0 mL, 18 mmol) was added. The reaction was
stirred at RT and followed by TLC, then poured into a
separatory funnel with dichloromethane (20 mL). The
mixture was washed with water (10 mL). The aqueous
was then extracted twice with dichloromethane (10 mL
each). The organics were combined and washed with sat-
urated sodium bicarbonate (10 mL) and then saturated
sodium chloride (10 mL). The organic was dried over
sodium sulfate and concentrated under vacuum to give a
crude mixture. Chromatography on 30-g silica gel with
mixtures of ethyl acetate and hexanes gave yellow oil
(0.9879 g), which could be solidified by dissolving in dic-
hloromethane and then removing the solvent. Recrystal-
lization from a mixture of 2-propanol and water gave a
small amount of impure yellow solid (0.0494 g). Slow
evaporation of the mother liquor then gave large,
1645.3 (C═O). UV/Vis (CH3CN): λmax
:
283 nm
(shoulder at approximately 313 nm). Rf (30% EtOAc/
hexanes) = 0.47.
4.3.10 | 3-(4-Methoxyphenyl)-2-phenyl-
2,3-dihydro-4H-1,3-benzothiazin-
4-one (1l)[22]
After chromatography on 30-g silica gel with mixtures of
ethyl acetate and hexanes, recrystallization from ethanol
gave pale yellow solid (0.7222 g, 35% yield). mp: 92ꢀC-
3
96ꢀC. 1H NMR (CDCl3): δ (ppm): 8.22 (1H, d, JHH
3
7.8 Hz, Ar connected to C5), 7.41 (2H, d, JHH 7.8 Hz),
7.33 (1H, m), 7.28-7.23 (7H, m), 7.17 (1H, d, 3JHH 7.8 Hz),
3
6.89 (2H, d, JHH 8.8 Hz), 5.99 (1H, s, C2), 3.81 (3H, s,
OCH3). 13C NMR (CDCl3): δ (ppm): 164.0 (C═O), 158.4,
139.5, 135.4, 133.2, 132.3, 130.4, 129.5, 128.5, 128.3, 114.4,
65.3 (C2), 55.5 (OCH3). HRMS (m/z): [M + H]+ of
348.10682 is consistent with calculated [M + H]+ of
348.10528. IR (neat, cm−1): 1650.7 (C═O). UV/Vis

8
SILVERBERG ET AL.
[12] M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr. Opin. Chem.
Biol. 2010, 14, 347. https://doi.org/10.1016/j.cbpa.2010.02.018.
[13] B. Loev, J. Org. Chem. 1963, 28, 2160. https://doi.org/10.1021/
jo01043a516.
[14] L. J. Silverberg, C. N. Pacheco, A. Lagalante, K. C. Cannon,
J. T. Bachert, Y. Xie, L. Baker, J. A. Bayliff, Intl. J. Chem.
(Toronto, ON, Can.) 2015, 7(2), 150. https://doi.org/10.5539/ijc.
v7n2p150.
[15] H. P. Yennawar, R. V. Bendinsky, D. J. Coyle, A. S. Cali,
L. J. Silverberg, Acta Cryst. 2014, E70, o465. https://doi.org/10.
1107/S1600536814005881.
[16] L. J. Silverberg, J. Tierney, C. Pacheco, A. Lagalante,
J. T. Bachert, J. A. Bayliff, R. V. Bendinsky, A. S. Cali,
L. Chen, A. D. Cooper, Minehan, M. J., C. R. Mroz,
D. J. Noble, A. K. Weisbeck, Y. Xie, Z. Yang Arkivoc 2016,
2016, (vi), 122–143. https://doi.org/10.24820/ark.5550190.
p009.875
translucent, slightly yellow crystals (0.3453 g, 17% yield).
1
mp: 95ꢀC-106ꢀC. H NMR (CDCl3): δ (ppm): 8.23 (1H, d,
3
3JHH 7.9 Hz, Ar connected to C5), 7.43 (2H, d, JHH
7.3 Hz), 7.37-7.17 (8H, m), 7.18 (2H, m), 6.03 (s, 1H, C2),
2.36 (s, 3H, CH3). 13C NMR (CDCl3): δ (ppm): 163.9
(C═O), 140.0, 139,6, 137.1, 133.3, 132.3, 130.4, 129.8,
128.4, 128.2, 127.7, 126.6, 126.4, 125.8, 65.3 (C2), 21.1
(CH3). HRMS (m/z): [M + H]+ of 332.11191 is consistent
with calculated [M + H]+ of 332.11036. IR (neat,
cm−1): 163.5 (C═O). UV/Vis (CH3CN): λmax: 271 nm
(shoulder at approximately 313 nm). Rf (15% EtOAc/
hexanes) = 0.24.
ACKNOWLEDGMENTS
The authors thank SP Controls, Inc., for summer support
of D.J.C. and R.V.B.; Euticals, Inc. (AMRI), for the gift of
T3P in 2-methyltetrahydrofuran; and Pennsylvania State
University Schuylkill Campus for financial support.
[17] H. Wissmann, H. J. Kleiner, Angew. Chem. Int. Ed. 1980,
19, 133.
[18] A. A. Waghmare, R. M. Hindupur, H. N. Pati, Rev. J. Chem.
2014, 4, 53.
[19] J. R. Dunetz, Y. Xiang, A. Baldwin, J. Ringling, Org. Lett. 2011,
13, 5048. https://doi.org/10.1021/ol201875q.
[20] H. P. Yennawar, A. S. Cali, Y. Xie, L. J. Silverberg,
Acta Cryst. 2015, E71, 414. https://doi.org/10.1107/
S2056989015004545.
[21] H. P. Yennawar, L. J. Silverberg, M. J. Minehan, J. Tierney,
Acta Cryst. 2013, E69, o1679. https://doi.org/10.1107/
S1600536813028389.
[22] L. J. Silverberg, H. P. Yennawar, D. J. Coyle. D. J. Noble,
Z. Yang, Acta Cryst. 2016, E72, 1108–1112. https://doi.org/10.
1107/S2056989016011002
[23] H. P. Yennawar, M. J. Buchwalter, B. K. Colburn,
L. J. Silverberg, Acta Cryst. 2018, E74, 363. https://doi.org/10.
1107/S2056989018002049.
[24] C. Kitsiou, W. P. Unsworth, G. Coulthard, R. J. K. Taylor, Tet-
rahedron 2014, 70, 7172. https://doi.org/10.1016/j.tet.2014.04.
06627.
[25] W. P. Unsworth, C. Kitsiou, R. J. K. Taylor, Org. Lett. 2013, 15,
258. https://doi.org/10.1021/ol303073b.
[26] L. J. Silverberg, D. J. Coyle, K. C. Cannon, R. T. Mathers,
J. A. Richards, J. Tierney, J. Chem. Educ. 2016, 93, 941. https://
doi.org/10.1021/acs.jchemed.6b00056.
ORCID
Lee J. Silverberg https://orcid.org/0000-0002-7353-1289
Carlos Pacheco https://orcid.org/0000-0002-5607-5517
Peter Scholl https://orcid.org/0000-0002-8870-3266
Hany F. Sobhi https://orcid.org/0000-0002-7389-4936
REFERENCES
[1] Z. Mei, L. Wang, W. Lu, C. Pang, T. Maeda, W. Peng,
M. Kaiser, I. El Sayed, T. Inokuchi, J. Med. Chem. 2013, 56,
1431. https://doi.org/10.1021/jm300887b.
[2] Q. Li, C. Li, X. Lu, H. Zhang, H. Zhu, Eur. J. Med. Chem.
2012, 50, 288. https://doi.org/10.1016/j.ejmech.2012.
02.007.
[3] S. Wang, K. Fang, G. Dong, S. Chen, N. Liu, Z. Miao, J. Yao,
J. Li, W. Zhang, C. Sheng, J. Med. Chem. 2015, 58, 6678.
https://doi.org/10.1021/acs.jmedchem.5b00910.
[4] M. M. Kamel, H. I. Ali, M. M. Anwar, N. A. Mohamed,
A. M. M. Soliman, Eur. J. Med. Chem. 2010, 45, 572. https://
doi.org/10.1016/j.ejmech.2009.10.044.
[5] L. Popiolek, A. Biernasiuk, A. Malm, J. Heterocycl. Chem.
2016, 53, 479. https://doi.org/10.1002/jhet.2429.
[6] F. Jeng, X. Li, J. Shao, M. Zhu, Y. Li, C. Hua, L. Xiaoliu, Chin.
J. Org. Chem. 2015, 35, 1370. https://doi.org/10.6023/
cjoc201412053.
[7] Y. Hou, S. Xing, J. Shao, Z. Yin, L. Hao, T. Yang, H. Zhang,
M. Zhu, H. Chen, X. Li, Carbohydr. Res. 2016, 429, 105–, and
references cited therein. https://doi.org/10.1016/j.carres.2016.
02.011.
[8] Z. M. Nofal, E. A. Soliman, A. El-Karim, M. I. El-Zahar,
A. M. Srour, S. Sethumadhavan, T. J. Maher, J. Heterocycl.
Chem. 2014, 51, 1797. https://doi.org/10.1002/jhet.1886.
[9] A. H. Mandour, E. R. El-Sawy, M. S. Ebid, Z. G. El-Sayed,
Egypt. J. Chem. 2007, 50, 555.
[27] H. P. Yennawar, L. J. Silverberg, Acta Cryst. 2014, E70, o133.
https://doi.org/10.1107/S1600536814000324
2015, E71, e5.
Corrigendum:
[28] H. P. Yennawar, H. G. Bradley, K. C. Perhonitch,
H. E. Reppert, L. J. Silverberg, Acta Cryst. 2018, E74, 454.
https://doi.org/10.1107/S2056989018003444.
[29] Unpublished results.
[30] A. Roe, J. A. Montgomery, J. Am. Chem. Soc. 1953, 75, 910.
https://doi.org/10.1021/ja01100a040.
[31] H. Naeimi, F. Salima, K. Rabiei, J. Mol. Cat. A: Chem. 2006,
260, 100. https://doi.org/10.1016/j.molcata.2006.06.055.
[32] P. M. Maginnity, J. L. Eisenmann, J. Am. Chem. Soc. 1952, 74,
6119. https://doi.org/10.1021/ja01143a518.
[33] J. S. Bennett, K. L. Charles, M. R. Miner, C. F. Heuberger,
E. J. Spina, M. F. Bartels, T. Foreman, Green Chem. 2009, 11,
166. https://doi.org/10.1039/B817379F.
[10] A. Zarghi, T. Zebardast, B. Daraie, M. Hedayati, Bioorg. Med.
Chem. 2009, 17, 5369. https://doi.org/10.1016/j.bmc.2009.06.056.
[11] L. J. Silverberg, Q. J. Moyer, Arkivoc 2019, 2019, (i), 139.
https://doi.org/10.24820/ark.5550190.p010.788.

SILVERBERG ET AL.
9
[34] S. Jia, D. Xing, D. Zhang, W. Hu, Angew. Chem.
Int. Ed. 2014, 53, 13098. https://doi.org/10.1002/anie.
201406492.
[35] A. L. Iglesias, J. J. Garcia, J. Mol. Cat. A: Chem. 2009, 298, 51.
https://doi.org/10.1016/j.molcata.2008.10.003.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[36] A. Simion, C. Simion, T. Kanda, S. Nagashima, Y. Mitoma,
T. Yamada, K. Mimura, M. Tashiro, J. Chem. Soc., Perkin
Trans. January 17, 2001, 2001, 2071–2078. https://doi.org/10.
1039/B102749M
[37] M. Rai, J. Ind, Chem. Soc. 2006, 83, 208.
[38] L. Jiang, L. Jin, H. Tian, X. Yu, Q. Xu, Chem. Commun. 2011,
47, 10833. https://doi.org/10.1039/C1CC14242A.
How to cite this article: Silverberg LJ,
Pacheco C, Sahu D, et al. T3P-promoted synthesis
of a series of novel 3-aryl-2-phenyl-2,3-dihydro-4H-
1,3-benzothiazin-4-ones. J Heterocyclic Chem. 2020;
1–9. https://doi.org/10.1002/jhet.3904