P(III)-Mediated Cascade C-N/C-S Bond Formation: A Protocol towards the Synthesis of N,S-Heterocycles and Spiro Compounds

Article abstract of DOI:10.1002/adsc.202001149

A P(III)-mediated entry towards construction of C?N/C?S bond has been devised. The developed heterocyclization method was exercised for the synthesis of a diverse range of N,S-heterocycles and related spiro molecules. P(NMe₂)₃ revealed the maximum efficacies under the aerobic reaction conditions and a spectrum of bis-nucleophiles, and isothiocyanates were tolerated well to serve the access of manifold immense molecules. (Figure presented.).

Full text of DOI:10.1002/adsc.202001149

Title: P(III)-Mediated Cascade C-N/C-S Bond Formation: A Protocol
towards the Synthesis of N,S-Heterocycles and Spiro
Compounds
Authors: Saibabu Polina, V. P. Rama Kishore Putta, Raghuram
Gujjarappa, Virender Singh, Prasad Pralhad Pujar, and
Chandi Malakar
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001149
Link to VoR: https://doi.org/10.1002/adsc.202001149

10.1002/adsc.202001149
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
P(III)-Mediated Cascade C-N/C-S Bond Formation: An
Protocol towards the Synthesis of N,S-Heterocycles and Spiro
Compounds
Saibabu Polina,a V. P. Rama Kishore Putta,a Raghuram Gujjarappa,b Virender Singh,c
Prasad Pralhad Pujar,a* and Chandi C. Malakarb*
a
Department of Chemistry, CHRIST (Deemed to be University), Bangalore - 560029, India
Phone: 080-40129313, Fax: +91 8040129000, Email: prasad.pujar@christuniversity.in
Department of Chemistry, National Institute of Technology Manipur, Langol, Imphal - 795004, Manipur, India
b
Phone: (+91) 0385-2058566, Fax: (+91) 0385-2445812, Email: chdeepm@gmail.com; cmalakar@nitmanipur.ac.in
Department of Chemistry, Central University of Punjab, Bathinda, 151001, Punjab, India
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A P(III)-mediated entry towards construction of bis-nucleophiles, and isothiocyanates were tolerated well to
C-N/C-S bond has been devised. The developed serve the access of manifold immense molecules.
heterocyclization method was exercised for the synthesis of a
diverse range of N,S-heterocycles and related spiro
molecules. P(NMe2)3 revealed the maximum efficacies under
the aerobic reaction conditions and a spectrum of
Keywords: Benzothiazin-4-ones; Cascade reaction; N,S-
heterocycles; P(NMe2)3; Spiro compounds
1-azaspiro compounds are barely explored, albeit
their medicinal importance.[7] In continuation of our
research in this area,[2f] here we have reported
P(NMe2)3-mediated annulation reactions of bis-
nucleophiles and isothiocyanates towards the
preparation of diversified N,S-heterocycles (Scheme
1).
Introduction
Nitrogen and sulphur containing heterocycles play an
impeccable and irreplaceable role in the field of
medicinal chemistry owing to their unique
pharmacological
properties.[1-7]
In
particular,
heterocyclic moieties such as benzothiazinones,
benzothiazines, pyrrolo[1,2-c]thiazoles and 3-thia-1-
azaspiro cores are well-recognized for their broad
spectrum
of
biological
properties.[1,3-7]
Benzothiazinones are eminently explored for their in
vitro inhibition of monoacylglycerol lipase (MGL)
activity,[5b] antagonizing adenosine receptors (A2A
ARs) and inhibiting monoamine oxidase B (MAO-
B).[5c,e] Albeit, these scaffolds possess vital
pharmacological properties, their synthetic strategies
have been rarely investigated. The synthesis of
benzothiazinones are largely accomplished by the
cyclization of aroylthioureas in presence of conc.
H2SO4.[5c,e,8] Our research group has recently reported
the synthesis of benzothiazines by employing T3P
(2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-
2,4,6-trioxide)-mediated cyclization of 2-amino-
arylalkyl alcohols with isothiocyanates.[2f] Afar from
these protocols, several other useful approaches
towards the preparation of benzothiazine motifs are
known.[3e,9] Likewise, the synthesis of pyrrolo[1,2-
c]thiazoles was realized by the cyclization of prolinol
derivatives with isothiocyanates in presence of conc.
HCl.[5f,6a,c] In contrast, structurally enthralling 3-thia-
Scheme 1. Approaches towards the synthesis of various
N,S-heterocycles.
1
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10.1002/adsc.202001149
Advanced Synthesis & Catalysis
a) All reactions were performed using 1.0 mmol 1a and 1.1
Results and Discussion
b)
mmol 2a in 2 mL of solvent at 25 °C under air. Isolated
yields. c) Conversion was monitored by LC−MS
We initiated our experiments by considering
anthranilic acid (1a) and benzoyl isothiocyanate (2a)
as model substrates. At the onset, we have screened
various organophosphine (PR3) reagents such as
trimethyl phosphite (P(OMe)3), dimethylphosphine
To our dismay, most of the screened reagents were
inactive for the formation of desired product 4aa,
rather the reaction was terminated at the intermediate
3aa stage. Surprisingly, among the screened
phosphine reagents, the P(NMe2)3 (HMPT,
Hexamethylphosphorous triamide) showed greater
efficacy in terms of conversion (91%) and yield
(83%). Notably, the reaction conditions were found
competent even with reduced amounts of base and
also in absence of base to obtain product 4aa in
similar yields of 83% and 86% respectively (entries
9-10). Upon screening of solvents (entries 11-16), it
was found that MeCN facilitates the formation of
product 4aa in higher yield of 93% (entry 15).
However, when the reaction was performed using
reduced amounts of HMPT, the unsuccessful results
were obtained (entries 17-18).
(PHMe2),
trimethylphosphine
(PPh3),
tributylphosphine
(PnBu3),
(PMe3), triphenylphosphine
2,4,6-tripropyl-1,3,5,2,4,6-
trioxatriphosphorinane-2,4,6-trioxide
hexamethylphosphoramide (HMPA)
hexamethylphosphorous triamide (HMPT) towards
the formation of the product benzothiazinone 4aa
(entries 1-8).
(T3P),
and
Table 1. Optimization of reaction conditions.a)
After screening the reaction conditions, we have
examined the scope of different 2-aminoaryl
carboxylic acids 1a-h with benzoyl isothiocyanate
(2a) to obtain diverse range of benzothiazinones 4aa-
4ha in yields up to 95% (Scheme 2). The developed
reaction conditions proved to be efficient for the
preparation of thiazinone derivatives 4ia-ka in good
to excellent yields with high functional group
tolerance.
Entry
Reaction conditions
%Yield 4aab)
(% conv.)c)
0 (trace)
1
2
3
4
5
6
7
8
9
P(OMe)3 (2 equiv.), Et3N (2.2
equiv.), MeCN, 8 h
PHMe2 (2 equiv.), Et3N (2.2
equiv.), MeCN, 8 h
0 (trace)
0 (<20)
0 (<15)
0 (trace)
67 (80)
0 (<20)
83 (91)
83 (94)
PnBu3 (2 equiv.), Et3N (2.2
equiv.), MeCN, 8 h
PMe3 (2 equiv.), Et3N (2.2
equiv.), MeCN, 8 h
PPh3 (2 equiv.), Et3N (2.2
equiv.), THF, 6 h
T3P (1.1 equiv.), Et3N (2.2
equiv.), MeCN, 8 h
HMPA (1.1 equiv.), Et3N (2.2
equiv.), PhMe, 16 h
HMPT (1.1 equiv.), Et3N (2.2
equiv.), PhMe, 4 h
HMPT (1.1 equiv.), Et3N (1.1
equiv.), PhMe, 4 h
10
11
HMPT (1.1 equiv.), PhMe, 4 h 86 (98)
HMPT (1.1 equiv.), EtOAc, 6
h
55 (72)
12
13
HMPT (1.1 equiv.), CH2Cl2, 6 46 (63)
h
Scheme 2. Scope of thiazinones.
HMPT (1.1 equiv.), DMSO, 6
h
31 (47)
14
15
HMPT (1.1 equiv.), DMF, 3 h
HMPT (1.1 equiv.), MeCN,
0.5 h
40 (60)
93 (100)
16
17
HMPT (1.1 equiv.), THF, 3 h
HMPT (0.75 equiv.), MeCN,
0.5 h
85 (95)
74 (90)
18
HMPT (0.50 equiv.), MeCN,
0.5 h
52 (70)
2
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10.1002/adsc.202001149
Advanced Synthesis & Catalysis
Scheme 3. Scope of different isothiocyanates 2.
Scheme 5. Scope of isothiocyanates 2 towards the
synthesis of benzothiazines 6.
Thereafter, we focused on elaborating the scope
of the reaction conditions with differently substituted
isothiocyanates 2d-h (Scheme 3). The aromatic
isothiocyanates with electron rich (methyl, methoxy)
as well as electron poor (F, CF3) functional groups
performed well under optimal reaction conditions by
delivering the products 4ab-ag in excellent yields.
Alkyl isothiocyanate 2h also reacted in a desired
pattern to produce 4ah in 88% yield.
Further, in order to expand the scope of the
developed methodology, variety of 2-aminobenzyl
alcohols 5a-h were investigated for reaction with
benzoyl isothiocyanate (2a). As a result, we have
obtained the corresponding benzothiazine derivatives
6aa-ha in the range of 88-97% yields (Scheme 4).
Moreover, 2-aminobenzyl alcohol (5a) was treated
with aryl/alkyl isothiocyanates 2b-d, h, j-m
accommodated with various functional groups to
afford the corresponding benzothiazines 6ab-ad, ah-
am in excellent yields (Scheme 5).
While identifying the multiple dimensions of
developed approach, we have come across towards
the synthesis of pyrrolo[1,2-c]thiazoles (8aa and ai)
and thiazolo[3,4-a]pyridines (8ba and ci) skeletons
by employing l-prolinol (7a), 2-piperidinemethanol
(7b), (±)-pipecolinic acid (7c) derivatives and
isothiocyanates 2a, i as substrates (Scheme 6). The
developed reaction conditions demonstrated excellent
proficiency in achieving biologically potential N,S-
heterocycles 8 in yields up to 94%.
Scheme 6. Synthesis of pyrrolo[1,2-c]thiazoles and
thiazolo[3,4-a]pyridines.
Scheme 4. Scope of 2-aminobenzyl alcohols 5a-h.
Scheme 7. Synthesis of N,S-spiroheterocycles 10.
3
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10.1002/adsc.202001149
Advanced Synthesis & Catalysis
To explore the broader application of the devised
method, we were encouraged to realize the amino
acid derivatives 9 as starting materials to construct
the rarely explored N,S-spiroheterocycles 10 (Scheme
7). Interestingly, it was found that the developed
approach was equally efficient to furnish N,S-
spirocyclic frameworks of various ring sizes in good
yields. It was also observed that the compound 10ba
was existing in an inseparable keto-enol tautomeric
form which was confirmed by NMR spectra.
After demonstrating a broad range of substrate
scope, we have attempted to propose a plausible
reaction mechanism for this chemical transformation.
To fulfil this purpose, we have executed admissible
control experiments. To begin with, we have carried
out the reaction of anthranilic acid (1a) and benzoyl
isothiocyanate (2a) to obtain intermediate 3aa in 95%
isolated yield under HMPT-free reaction conditions
(Scheme 8, Eq. 1). The isolated intermediate 3aa is
further subjected to standard reaction conditions to
obtain the desired product 4aa in 92% yield (Scheme
8, Eq. 2). The obtained results reinforced the
formation of thiourea intermediate 3aa during the
reaction pathway. Alternatively, a reaction of
anthranilic acid (1a) under standard reaction
conditions resulted in an amide derivative 11a in 76%
yield (Scheme 8, Eq. 3). The formation of amide 11a
was attributed to the acid-amine coupling reaction
between anthranilic acid 1a and the in-situ liberated
N,N-dimethylamine (12a) during the reaction process.
Simultaneously, we have also carried out the reaction
of 1a and 2a under standard reaction conditions in
presence of N2 atmosphere. Surprisingly, the reaction
conditions generated the desired product 4aa with
mere 31% yield (Scheme 8, Eq. 4). Finally, to
elucidate the prospect of phosphine reagent under
aerobic conditions, we have carried out the reaction
of anthranilic acid (1a) and benzoyl isothiocyanate
(2a) under HMPA-mediated reaction conditions. To
our disappointment, the reaction conditions were
found to be inefficient in producing 4aa (Scheme 8,
Eq. 5). The above obtained results guided us to
understand the following aspects, (i) The reagent
P(NMe2)3 is not getting converted to OP(NMe2)3 via
aerial oxidation. (ii) The aerial oxygen is mandatory
for acquiring the desired product in higher yields. (iii)
The addition of HMPT to the reaction mixture leads
to the liberation of Me2NH (12a).
Scheme 8. Control experiments.
With these preliminary results in hand, we
intended to gain further insights into the reaction
mechanism. To achieve this motive, we have
performed the reaction of anthranilic acid (1a)
([M+H]+ = 138.0) and benzoyl isothiocyanate (2a)
([M]+ = 162.9) under the standard reaction conditions.
The course of the reaction was monitored by liquid
chromatography-mass spectrometry (LC–MS) after
an interval of 15 min, 30 min and 60 min. The mass-
spectroscopic data revealed the possible participation
of intermediates 3aa ([M+H]+ = 301.1) to obtain the
desired product 4aa ([M+H]+ = 283.1) along with the
formation of byproduct C ([M]+ = 151.1) during the
course of reaction (details of mass spectrometric data
have been provided in Figure 1, SI).
On the basis of above experimental evidences
and literature reports,[10] a plausible mechanism has
been depicted (Scheme 9). According to the proposed
mechanism, thiourea intermediate 3aa ([M+H]+ =
301.1) would result by the reaction of anthranilic acid
(1a) ([M+H]+ = 138.0) and benzoyl isothiocyanate
(2a) ([M]+ = 162.9). The tendency of P(NMe2)3
towards hydroxyl functionality enables the rapid
discharge of N,N-dimethylamine (12a) moiety and
subsequent oxidation of phosphine by aerial oxygen
results in the formation of intermediate A. Next, the
intramolecular heterocyclization via nucleophilic
attack of sulphur-atom over carbonyl carbon leads to
the formation of intermediate B. Subsequent
4
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10.1002/adsc.202001149
Advanced Synthesis & Catalysis
recorded at 400 (100) MHz on a Brucker spectrometer
elimination of phosphorodiamidate derivative C
([M]+ = 151.1) and deprotonation provides the
desired product 4aa ([M+H]+ = 283.1).
1
using CDCl3 and DMSO-d6 as a solvent. The H and 13C
chemical shifts were referenced to residual solvent signals
at H/C 7.26/77.28 (CDCl3) and H/C 2.51/39.50 (DMSO-d6)
relative to TMS as internal standards. Coupling constants J
[Hz] were directly taken from the spectra and are not
averaged. Splitting patterns are designated as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), overlapped
and br (broad).
General Experimental Procedure for the Synthesis of
4H-3,1-Benzothiazin-4-ones 4aa-ka and 4ab-ah
A 10 mL round bottom flask was charged with 2-amino-
aryl/alkyl carboxylic acids 1a-k (1.0 mmol), aryl or alkyl
isothiocyanates 2a-h (1.0 mmol) in MeCN (2 mL) and the
reaction mixture was stirred at room temperature (25 °C)
for 15 to 30 mins. The reaction progress was monitored by
TLC (SiO2, Hexane/EtOAc = 8:2) and LC-MS. The TLC
and LCMS analysis showed the absence of both the
starting materials and the formation of thiourea intermeiate.
The reaction mixture was then added with P(NMe2)3 (1.1
mmol) and the reaction mixture was stirred at room
temperature (25 °C) for 5-210 mins. After completion of
the reaction (progress was monitored by TLC; SiO2,
Hexane/EtOAc = 8:2 and LC-MS), the recation mixture
was extracted with ethyl acetate (3 × 15 mL), water
(20 mL). The combined organic layer was washed with
sodium thiosulphate solution (3 × 10 mL) and dried over
anhydrous Na2SO4. Solvent was removed under reduced
pressure and the remaining residue was purified over
CombiFlash MPLC using Hexane/EtOAc = 70:30 as an
eluent to obtain the desired 4H-3,1-benzothiazin-4-ones
Scheme 9. Proposed mechanism for P(NMe2)3-mediated
heterocyclization reaction.
Conclusion
4aa-ka and
4ab-ah in high yields.
In conclusion, we have established a facile
protocol towards the synthesis of diversified N,S-
General Experimental Procedure for the Synthesis of 2-
Amino-1,3-benzothiazines 6aa-ha and 6ab-ad, ah-am
heterocycles
using
P(NMe2)3–mediated
heterocyclization reaction between bis-nucleophiles
and isothiocyanates under aerobic conditions. This
process provides a convenient synthetic route to
pharmaceutically valuable 2-(acyl)amino-4H-3,1-
benzothiazin-4-ones and related thienothiazinones.
The devised method was also beneficial for the
synthesis of very rarely explored pyrrolo[1,2-
c]thiazoles, thiazolo[3,4-a]pyridines and N,S-
spiroheterocycles. The reaction conditions showed
excellent functional group tolerance and delivered the
desired products in yields up to 97%. The developed
organophosphine-mediated approach was well
understood by adequate control experiments and
mass-spectroscopic data.
A 10 mL round bottom flask was charged with 2-amino-
aralkyl alcohols 5a-h (1.0 mmol), aryl or alkyl
isothiocyanates 2a-d, h-m (1.0 mmol) in MeCN (2 mL)
and the reaction mixture was stirred at room temperature
(25 °C) for 15 to 30 mins. The reaction progress was
monitored by TLC (SiO2, Hexane/EtOAc = 8:2) and LC-
MS. The TLC and LCMS analysis showed the absence of
both the starting materials and the formation of thiourea
intermeiate. The reaction mixture was then added with
P(NMe2)3 (1.1 mmol) and the reaction mixture was stirred
at room temperature (25 °C) for 15-90 mins. After
completion of the reaction (progress was monitored by
TLC; SiO2, Hexane/EtOAc = 8:2 and LC-MS), the recation
mixture was extracted with ethyl acetate (3 × 15 mL),
water (20 mL). The combined organic layer was washed
with sodium thiosulphate solution (3 × 10 mL) and dried
over anhydrous Na2SO4. Solvent was removed under
reduced pressure and the remaining residue was purified
over CombiFlash MPLC using Hexane/EtOAc = 70:30 as
an eluent to obtain the desired 2-amino-1,3-benzothiazines
Experimental Section
6aa-ha and
6ab-ad, ah-am in high yields.
General Information
General Experimental Procedure for the Synthesis of
Pyrrolo[1,2-c]thiazoles (8aa and ai) and Thiazolo[3,4-
a]pyridines (8ba and ci)
All starting materials were purchased from commercial
suppliers (Sigma-Aldrich, Alfa-Aesar, SD fine chemicals,
Merck, HI Media) and were used without further
purification unless otherwise indicated. All reactions were
performed in a 10 mL round bottom flask with magnetic
stirring. Solvents used in extraction and purification were
distilled prior to use. Thin-layer chromatography (TLC)
was performed on TLC plates purchase from Merck.
Compounds were visualized with UV light (λ = 254 nm)
and/or by immersion in KMnO4 staining solution followed
by heating. Products were purified by CombiFlash MPLC.
Melting points were determined in open capillary tubes on
EZ-Melt automated melting point apparatus and are
uncorrected. All HRMS are recorded using 6545 QTOF
LC/MS, Agilent instrument equipped with an auto sampler
in EI-QTOF method and LC-MS are recorded in APCI
A 10 mL round bottom flask was charged with l-prolinol
(7a) or 2-piperidinemethanol (7b) or (±)-pipecolinic acid
(7c) (1.0 mmol), bezoyl isothiocyanates (2a) or phenyl
isothiocyanates (2i) (1.0 mmol) in MeCN (2 mL) and the
reaction mixture was stirred at room temperature (25 °C)
for 15 to 30 mins. The reaction progress was monitored by
TLC (SiO2, Hexane/EtOAc = 8:2) and LC-MS. The TLC
and LCMS analysis showed the absence of both the
starting materials and the formation of thiourea intermeiate.
The reaction mixture was then added with P(NMe2)3 (1.1
mmol) and the reaction mixture was stirred at room
temperature (25 °C) for 15-90 mins. After completion of
the reaction (progress was monitored by TLC; SiO2,
Hexane/EtOAc = 8:2 and LC-MS), the recation mixture
method in acetonitrile solvent. H (13C) NMR spectra were
1
5
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10.1002/adsc.202001149
Advanced Synthesis & Catalysis
was extracted with ethyl acetate (3 × 15 mL), water
(20 mL). The combined organic layer was washed with
sodium thiosulphate solution (3 × 10 mL) and dried over
anhydrous Na2SO4. Solvent was removed under reduced
pressure and the remaining residue was purified over
CombiFlash MPLC using Hexane/EtOAc = 80:20 as an
eluent to obtain the desired pyrrolo[1,2-c]thiazoles (8aa
and ai) and thiazolo[3,4-a]pyridines (8ba and ci) in high
yields.
N-(7-chloro-4-oxo-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (4da) (Scheme 2): White solid; Rf = 0.50
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 284
1
mg (90%); m.p = 233.2-224.6 °C; H NMR (400 MHz,
DMSO-d6) δ = 12.44 (s, 1H), 8.03-8.00 (m, 3H), 7.63 (t, J
= 7.4 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.54-7.49 (m, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.4, 168.18,
156.54, 148.9, 141.18, 133.53, 132.44, 129.0, 128.93,
127.8, 127.57, 126.9, 118.67 ppm; MS (APCI): [M + 1]+ =
317.3 (100%); HRMS (ESI-QTOF, [M + H]+): calculated
for C15H10ClN2O2S: 317.0151; found: 317.0146.
General Experimental Procedure for the Synthesis of
N,S-spirocycles 10aa-da
N-(4-oxo-7-(trifluoromethyl)-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (4ea) (Scheme 2): Off-white solid; Rf =
0.55 (SiO2, Hexane/EtOAc = 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 315
A 10 mL round bottom flask was charged with 1-amino-1-
cycloalkylcarboxylic acids 9a-d, bezoyl isothiocyanates
(2a) (1.0 mmol) in MeCN (2 mL) and the reaction mixture
was stirred at room temperature (25 °C) for 30 mins. The
reaction progress was monitored by TLC (SiO2,
Hexane/EtOAc = 8:2) and LC-MS. The TLC and LCMS
analysis showed the absence of both the starting materials
and the formation of thiourea intermeiate. The reaction
mixture was then added with P(NMe2)3 (1.1 mmol) and the
reaction mixture was stirred at room temperature (25 °C)
for 15-90 mins. After completion of the reaction (progress
was monitored by TLC; SiO2, Hexane/EtOAc = 8:2 and
LC-MS), the recation mixture was extracted with ethyl
acetate (3 × 15 mL), water (20 mL). The combined organic
layer was washed with sodium thiosulphate solution (3 ×
10 mL) and dried over anhydrous Na2SO4. Solvent was
removed under reduced pressure and the remaining residue
1
mg (90%); H NMR (400 MHz, DMSO-d6) δ = 12.48 (br,
1H), 8.23 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8 Hz, 2H), 7.84-
7.80 (m, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.6 Hz,
2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.83,
167.91, 156.2, 148.1, 135.6 (q, J = 32.5 Hz), 133.6, 132.23,
129.6, 129.0, 128.9, 127.7, 126.6, 124.56 (q, J = 272.1 Hz),
122.0, 119.5 ppm; MS (APCI): [M + 1]+ = 351.0
(98.42%); HRMS (ESI-QTOF, [M + H]+): calculated for
C16H10F3N2O2S: 351.0415; found: 351.0411.
N-(4-oxo-4H-pyrido[2,3-d][1,3]thiazin-2-yl)benzamide
(4fa) (Scheme 2): Off-white solid; Rf = 0.45 (SiO ,
Hexane/EtOAc = 7:3); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 60:40); yield: 229 mg (81%);
was
purified
over
CombiFlash
MPLC
using
1
Hexane/EtOAc = 80:20 as an eluent to obtain the desired
N,S-spirocycles 10aa-da in high yields.
m.p = 211.8-212.6 °C; H NMR (400 MHz, DMSO-d6) δ
= 12.73 (br, 1H), 8.95 (s, 1H), 8.41 (d, J = 7.6 Hz, 1H),
8.07 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.55-7.51
(m, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 186.2,
168.76, 157.96, 157.16, 134.38, 133.62, 132.55, 129.19,
Analytical Data of Synthesized 4H-3,1-Benzothiazin-4-
ones 4aa-ka and 4ab-ah
128.96, 122.95, 115.88 ppm; MS (APCI): [M + 1]+
=
284.10 (100.00%); HRMS (ESI-QTOF, [M + H]+):
N-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)benzamide (4aa)
(Scheme 2): White solid; Rf = 0.60 (SiO2, Hexane/EtOAc
calculated for C14H10N3O2S: 284.0493; found: 284.0490.
=
8:2); purification system: CombiFlash MPLC
N-(4-oxo-4H-naphtho[2,3-d][1,3]thiazin-2-yl)benzamide
(4ga) (Scheme 2): Yellow solid; Rf = 0.60 (SiO2,
Hexane/EtOAc = 8:2); purification system: CombiFlash
MPLC (Hexane/EtOAc = 80:20); yield: 286 mg (86%);
(Hexane/EtOAc = 80:20); yield: 262 mg (93%); m.p =
168.1-169.1 °C; 1H NMR (400 MHz, DMSO-d6) δ = 13.24
(s, 1H), 8.07 (d, J = 8.0 Hz, 3H), 7.90 (dt, J = 8.0 Hz, 1H),
7.69-7.62 (m, 2H), 7.54 (t, J = 8.0 Hz, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6): δ = 185.11, 136.81, 133.47, 129.04,
128.96, 124.89, 119.92, 114.02 ppm; MS (APCI):[M + 1]+
= 282.90 (99.84%); HRMS (EI-QTOF, [M + H]+):
calculated for C15H11N2O2S: 283.0541; found: 283.0536.
1
m.p = 265.0-266.0 °C; H NMR (400 MHz, DMSO-d6) δ
= 12.16 (br, 1H), 8.79 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H),
8.17 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 8.0 Hz,
2H), 7.71 (t, J = 8.0 Hz, 1H), 7.66-7.58 (m, 2H), 7.53 (t, J
= 7.6 Hz, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ =
186.02, 171.98, 156.26, 141.99, 138.14, 135.28, 134.97,
133.71, 132.95, 132.17, 131.77 ppm; MS (APCI): [M + 1]+
= 333.3 (99.39%); HRMS (ESI-QTOF, [M + H]+):
calculated for C19H13N2O2S: 333.0697; found: 333.0694.
N-(7-methyl-4-oxo-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (4ba) (Scheme 2): White solid; Rf = 0.60
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 275
1
mg (93%); m.p = 181.2-182.4 °C; H NMR (400 MHz,
N-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d][1,3]thiazin-2-
yl)benzamide (4ha) (Scheme 2): White solid; Rf = 0.60
DMSO-d6) δ = 12.25 (br, 1H), 8.03 (d, J = 7.6 Hz, 2H),
7.93 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.51 (t, J
= 8.0 Hz, 2H), 7.43 (br, 1H), 7.33 (dd, J = 8.0 Hz, 1H),
2.44 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ =
184.51, 147.8, 133.4, 132.7, 129.01, 128.91, 128.8, 124.85,
117.75, 21.88 ppm; MS (APCI): [M + 1]+ = 297.10
(99.71%); HRMS (ESI-QTOF, [M + H]+): calculated for
C16H13N2O2S: 297.0697; found: 297.0690.
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 278
1
mg (88%); m.p = 251.1-252.3 °C; H NMR (400 MHz,
DMSO-d6) δ = 12.39 (s, 1H), 8.01 (d, J = 7.2 Hz, 2H), 7.63
(t, J = 7.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H), 2.34 (s, 6H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ = 177.78, 167.07,
163.3, 157.86, 133.4, 132.33, 129.11, 128.88, 119.76,
13.91, 12.7 ppm; MS (APCI): [M + 1]+ = 317.10
(99.28%); HRMS (ESI-QTOF, [M + H]+): calculated for
C15H13N2O2S2: 317.0418; found: 317.0415.
N-(7-methoxy-4-oxo-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (4ca) (Scheme 2): White solid; Rf = 0.50
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 296
1
(Z)-N-(8-oxo-5,6,7,8-tetrahydro-4H-1,3-thiazocin-2-
yl)benzamide (4ia) (Scheme 2): Yellow solid; Rf = 0.5
mg (95%); m.p = 186.2-187.4 °C; H NMR (400 MHz,
DMSO-d6) δ = 12.21 (br, 1H), 8.03 (d, J = 7.6 Hz, 2H),
7.99 (t, J = 7.2 Hz, 1H),7.63 (t, J = 7.2 Hz, 1H), 7.52 (t, J =
7.6 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 2.4 Hz,
1H), 3.91 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
= 183.1, 168.1, 165.7, 155.9, 149.7, 133.4, 132.7, 129.0,
128.9, 127.1, 115.7, 113.8, 110.6, 56.3 ppm; MS (APCI):
[M + 1]+ = 313.1 (99.75%); HRMS (ESI-QTOF, [M +
H]+): calculated for C16H13N2O3S: 313.0646; found:
313.0640.
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 194
1
mg (74%); m.p = 145.2-146.9 °C; H NMR (400 MHz,
DMSO-d6) δ = 12.99 (br, 1H), 7.84 (d, J = 7.2 Hz, 2H),
7.63 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.4 Hz, 2H), 4.06-4.03
(m, 2H), 2.52-2.48 (m, 2H), 1.83-1.75 (m, 4H) ppm; MS
(APCI): [M + 1]+ = 263.1 (91.6%); 13C NMR (100 MHz,
DMSO-d6) δ = 184.6, 174.76, 167.5, 134.11, 133.9, 129.6,
129.14, 51.17, 35.27, 23.19, 20.28 ppm; MS (APCI): [M +
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001149
Advanced Synthesis & Catalysis
1
1]+ = 317.10 (99.28%); HRMS (ESI-QTOF, [M + H]+):
m.p = 177.5-178.5 °C; H NMR (400 MHz, DMSO-d6) δ
= 10.19 (br, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.75 (t, J = 7.2
Hz, 1H), 7.62 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.34-7.22
(m, 3H), 6.67 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ = 183.99, 160.0, 151.96,
150.0, 140.98, 136.8, 130.0, 128.92, 125.28, 124.81,
117.82, 112.87, 109.58, 106.46, 55.47 ppm; MS (APCI):
[M + 1]+ = 285.1 (99.70%); HRMS (ESI-QTOF, [M +
H]+): calculated for C15H13N2O2S: 285.0697; found:
285.0693.
calculated for C13H15N2O2S: 263.0854; found: 263.0852.
N-(5-methyl-6-oxo-5,6-dihydro-4H-1,3-thiazin-2-
yl)benzamide (4ja) (Scheme 2): Sticky solid; Rf = 0.4
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 203
1
mg (82%); m.p = 196.0-197.1 °C; H NMR (400 MHz,
DMSO-d6) δ = 11.69 (br, 1H), 7.82 (d, J = 7.6 Hz, 2H),
7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 3.96 (dd,
J = 6, 5.6 Hz, 1H), 3.69 (t, J = 12.2 Hz, 1H), 3.15-3.09 (m,
1H), 1.15 (d, J = 7.2 Hz, 1H) ppm; 13C NMR (100 MHz,
2-((3-fluorophenyl)amino)-4H-benzo[d][1,3]thiazin-4-
DMSO-d6) δ = 181.5, 174.4, 170.87, 134.95, 133.19, 129.7, one (4af) (Scheme 3): White solid; Rf = 0.5 (SiO ,
128.99, 50.09, 35.14, 12.36 ppm; HRMS (ESI-QTOF, [M
+ H]+): calculated for C12H13N2O2S: 249.0697; found:
249.0694.
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 80:20); yield: 245 mg (90%);
1
m.p = 188.2-188.4 °C; H NMR (400 MHz, DMSO-d6) δ
= 10.38 (br, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.6
Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.41-
7.33 (m, 2H), 6.90 (dt, J = 7.6, 2.0 Hz, 1H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ = 183.7, 162.55 (d, J =
240.2 Hz), 151.8, 149.65, 141.57, 141.46, 136.8, 130.84,
130.75, 129.0, 125.59, 124.82, 117.9, 116.17, 110.18 (d, J
= 20.9 Hz), 107.37 (d, J = 26.4 Hz) ppm; MS (APCI): [M
+ 1]+ = 273.20 (96.45%); HRMS (ESI-QTOF, [M + H]+):
calculated for C14H10FN2OS: 273.0497; found: 273.0494.
(Z)-N-(1-methyl-4-oxo-1H-benzo[d][1,3]thiazin-2(4H)-
ylidene)benzamide (4ka)[8d] (Scheme 2): Off-white solid;
Rf = 0.4 (SiO2, Hexane/EtOAc = 8:2); purification
system: CombiFlash MPLC (Hexane/EtOAc = 80:20);
1
yield: 258 mg (87%); m.p = 265.0-266.0 °C; H NMR
(400 MHz, DMSO-d6) δ = 8.08 (d, J = 7.9 Hz, 1H), 8.02 (d,
J = 7.6 Hz, 2H), 7.95 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0
Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.55-7.47 (m, 3H), 4.00
(s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 173.7,
167.9, 158.6, 142.0, 137.0, 135.1, 131.93, 130.7, 129.75,
127.9, 125.57, 117.67, 117.3, 36.95 ppm; MS (APCI): [M
+ 1]+ = 297.1 (93.94%); HRMS (ESI-QTOF, [M + H]+):
calculated for C16H13N2O2S: 297.0697; found: 297.0695.
2-((4-(trifluoromethyl)phenyl)amino)-4H-
benzo[d][1,3]thiazin-4-one (4ag) (Scheme 3): Off-white
solid; Rf = 0.60 (SiO2, Hexane/EtOAc = 7:3); purification
system: CombiFlash MPLC (Hexane/EtOAc = 70:30);
1
yield: 296 mg (92%); m.p = 220-220.8 °C; H NMR (400
2-(p-tolylamino)-4H-benzo[d][1,3]thiazin-4-one (4ab)[11]
(Scheme 3): White solid; Rf = 0.4 (SiO2, Hexane/EtOAc =
MHz, DMSO-d6) δ = 10.53 (br, 1H), 8.06 (d, J = 6.8 Hz,
2H), 7.99 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.70
(d, J = 7.6 Hz, 2H), 7.57 (d, J = 8.0Hz, 1H), 7.37 (t, J = 6.8
Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 183.66,
151.69, 149.39, 143.44, 136.72, 129.0, 126.45, 125.7,
125.21 (q, J = 249.8 Hz), 123.21 (q, J = 31.8 Hz), 120.27,
117.94 ppm; MS (APCI): [M + 1]+ = 323.0 (99.73%);
8:2);
purification
system:
CombiFlash
MPLC
(Hexane/EtOAc = 80:20); yield: 241 mg (90%); m.p =
160.6-161.2 °C; 1H NMR (400 MHz, DMSO-d6) δ = 10.11
(br, 1H), 7.95 (d, J = 8 Hz, 1H), 7.73 (t, J = 8 Hz, 1H),
7.67 (d, J = 8 Hz, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.29 (t, J =
7.2 Hz, 1H), 7.16 (d, J = 8 Hz, 2H), 2.27 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ = 184.04, 152.2, 150.3,
137.2, 136.7, 133.18, 129.7, 128.81, 124.92, 124.8, 121.0,
117.73, 20.9 ppm; MS (APCI): [M + 1]+ = 269.0
(93.17%); HRMS (ESI-QTOF, [M + H]+): calculated for
C15H13N2OS: 269.0748; found: 269.0744.
HRMS (ESI-QTOF, [M
+
H]+): calculated for
C15H10F3N2OS: 323.0465; found: 323.0460.
Ethyl
(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)carbamate
(4ah) (Scheme 3): Off-white solid; Rf = 0.5 (SiO2,
Hexane/EtOAc = 8:2); purification system: CombiFlash
MPLC (Hexane/EtOAc = 70:30); yield: 220 mg (88%);
1
m.p = 111.8-113.0 °C; H NMR (400 MHz, DMSO-d6) δ
2-((2,4-dimethylphenyl)amino)-4H-
= 11.69 (br, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (dt, J = 6.8,
1.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz,
1H), 4.17 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, DMSO-d6) δ = 183.91, 153.44,
152.29, 147.59, 135.72, 128.95, 126.89, 125.0, 119.52,
62.79, 14.19 ppm; MS (APCI): [M+ 1]+ = 251.0 (99.45%);
benzo[d][1,3]thiazin-4-one (4ac) (Scheme 3): White
solid; Rf = 0.4 (SiO2, Hexane/EtOAc = 8:2); purification
system: CombiFlash MPLC (Hexane/EtOAc = 80:20);
1
yield: 254 (90%); m.p = 140.0-141.0 °C; H NMR (400
MHz, DMSO-d6) δ = 9.80 (br, 1H), 7.90 (br, 1H), 7.66 (t, J
= 7.6 Hz, 1H),7.27 (d, J = 8.0 Hz, 1H), 7.22-7.15 (m, 3H),
7.02 (br, 1H), 2.26 (s, 3H), 2.16 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ = 183.9, 155.38, 150.72, 136.72,136.2,
131.0, 127.85, 124.98, 124.2, 117.36, 20.92, 17.85 ppm;
MS (APCI): [M + 1]+= 283.20 (99.43%); HRMS (ESI-
QTOF, [M + H]+): calculated for C16H15N2OS: 283.0905;
found: 283.0901.
HRMS (ESI-QTOF, [M
+
H]+): calculated for
C11H11N2O3S: 251.0490; found: 251.0488.
Analytical Data of Synthesized 2-Amino-1,3-
benzothiazines 6aa-ha and 6ab-ad, ah-am
N-(4H-Benzo[d][1,3]thiazin-2-yl)benzamide
(Scheme 4); White solid; Rf = 0.60 (SiO , hexane/EtOAc
(6aa)[2f]
2-((2-methoxyphenyl)amino)-4H-benzo[d][1,3]thiazin-
4-one (4ad) (Scheme 3): White solid; Rf = 0.5 (SiO ,
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 80:20); yield: 273 mg (96%);
=
8:2); purification system: Com2biFlash MPLC
(hexane/EtOAc = 87:13); yield: 260 mg (97%); m.p 124-
125 °C (Lit[2f] 123-124 °C); H NMR (400 MHz, DMSO-
1
1
m.p = 176.0-177.0 °C; H NMR (400 MHz, DMSO-d6) δ
d6) δ = 11.69 (br s, 1H), 8.07 (d, J = 7.6 Hz, 2H), 7.55 (t, J
= 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.30-7.24 (m, 2H),
7.20 (dd, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 3.95 (s,
2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 172.4 (less
intense), 164.5 (less intense), 138.4 (less intense), 135.7
(less intense), 132.55, 129.31, 128.75, 128.54, 127.36,
125.24, 121.66, 28.21 ppm; HRMS (ESI-QTOF, [M +
H]+): calcd for C15H13N2OS, 269.0748; found, 269.0746.
= 9.61 (br, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.78 (br, 1H),
7.69 (t, J = 6.8 Hz, 1H), 7.34 (t, J = 8 Hz, 1H), 7.24-7.19
(m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H),
3.80 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ =
184.25, 154.65, 152.83, 150.41, 136.69, 128.54, 127.0,
126.3, 124.86, 124.5, 120.93, 117.53, 112.44, 56.14 ppm;
MS (APCI): [M + 1]+ = 285.10 (99.73%); HRMS (ESI-
QTOF, [M + H]+): calculated for C15H13N2O2S: 285.0697;
found: 285.0691.
N-(7-methyl-4H-benzo[d][1,3]thiazin-2-yl)benzamide
(6ba)[2f] (Scheme 4): Off-white solid; Rf = 0.60 (SiO ,
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (EtOAc/Hexane = 20:80); yield: 259 mg (92%);
2-((3-methoxyphenyl)amino)-4H-benzo[d][1,3]thiazin-
4-one (4ae) (Scheme 3): White solid; Rf = 0.5 (SiO ,
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 80:20); yield: 261 mg (92%);
1
m.p = 144.6-145.4 °C (Lit[2f] 145-146 °C); H NMR (400
MHz, DMSO-d6) δ = 11.61 (br, 1H), 8.07 (d, J = 7.2 Hz,
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001149
Advanced Synthesis & Catalysis
2H), 7.55 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.12
(d, J = 2.4 Hz, 1H), 7.00 (brs, 1H), 6.94 (dd, J = 7.6, 2.2
Hz, 1H), 3.90 (s, 2H), 2.27 (s, 3H) ppm; 13C NMR (100
MHz, DMSO-d6) δ = 170.2 (less intense), 137.9, 135.8,
132.5, 129.32, 128.73, 127.18, 125.86, 118.64, 28.0, 21.27
ppm; MS (APCI): [M + 1]+ = 283.1 (99%); HRMS (ESI-
QTOF, [M + H]+): calculated for C16H15N2OS: 283.0905;
found: 283.0900.
123.89, 121.27, 44.7 ppm; HRMS (ESI-QTOF, [M + H]+):
calculated for C21H17N2OS: 345.1061; found: 345.1063.
(Z)-N-(1-methyl-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-
ylidene)benzamide (6ha) (Scheme 4): Pale brown solid;
Rf = 0.50 (SiO , Hexane/EtOAc = 8:2); purification
system: CombiF2lash MPLC (Hexane/EtOAc = 85:15);
1
yield: 260 mg (92%); m.p = 178.8-181 °C; H NMR (400
MHz, DMSO-d6) δ = 8.17 (d, J = 7.9 Hz, 2H), 7.61 (tt, J =
7.3 Hz, 1H), 7.52 (t, J = 7.9 Hz, 2H), 7.45-7.37 (m, 3H),
7.25 (dt, J = 7.8 Hz, 1H), 3.93 (s, 2H), 3.82 (s, 3H) ppm;
13C NMR (100 MHz, DMSO-d6) δ = 174.1, 167.11,
140.58, 136.44, 132.68, 129.74, 128.87, 128.61, 126.87,
126.54, 125.21, 118.72, 37.82, 28.07 ppm; MS (APCI): [M
+ 1]+ = 283.1 (99.42%); HRMS (ESI-QTOF, [M + H]+):
calculated for C16H15N2OS: 283.0905; found: 283.0901.
N-(8-methyl-4H-benzo[d][1,3]thiazin-2-yl)benzamide
(6ca)[2f] (Scheme 4): Off-white solid; Rf = 0.60 (SiO ,
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 80:20); yield: 251 mg (89%);
1
m.p = 128.0-129.2 °C (Lit[2f] 127-128 °C); H NMR (400
MHz, DMSO-d6) δ = 11.59 (br, 1H), 8.02 (d, J = 5.6 Hz,
2H), 7.59 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H),
7.17-7.14 (m, 1H), 7.05 (d, J = 4.9 Hz, 2H), 3.93 (s, 2H),
2.31 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ =
170.1 (less intense), 138.7 (less intense), 134.5 (less
intense), 132.81, 129.97, 129.13, 128.79, 125.75, 124.98,
28.82, 17.74 ppm; MS (APCI): [M + 1]+ = 283.1
(99.10%); HRMS (ESI-QTOF, [M + H]+): calculated for
C16H15N2OS: 283.0905; found: 283.0902.
N-(p-tolyl)-4H-benzo[d][1,3]thiazin-2-amine
(6ab)[2f]
(Scheme 5): Off-white solid; Rf
=
0.60 (SiO2,
Hexane/EtOAc = 8:2); purification system: CombiFlash
MPLC (EtOAc /Hexane= 20:80); yield: 229 mg (90%);
1
m.p = 187.5-188.8 °C (Lit[2f] 188-189 °C); H NMR (400
MHz, DMSO-d6) δ = 9.35 (br, 1H), 7.70 (br, 2H), 7.22-
7.15 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.03-6.97 (m, 2H),
3.99 (s, 2H), 2.23 (s, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ = 150.7 (less intense), 145.0 (less intense),
131.67, 129.49, 128.34, 127.23, 123.63, 120.77, 120.29,
29.12, 20.88 ppm; MS (APCI): [M + 1]+ = 255.1
(99.10%); HRMS (ESI-QTOF, [M + H]+): calculated for
C15H15N2S: 255.0955; found: 255.0951.
N-(8-fluoro-4H-benzo[d][1,3]thiazin-2-yl)benzamide
(6da)[2f] (Scheme 4): Off-white solid; Rf = 0.50 (SiO ,
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 80:20); yield: 235 mg (82%);
1
m.p = 124.6-125.8 °C (Lit[2f] 124-125 °C); H NMR (400
MHz, DMSO-d6) δ = 11.95 (s, 1H), 8.00 (d, J = 7.9 Hz,
2H), 7.60 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H),
7.19-7.16 (m, 2H), 7.08-7.05 (m, 1H), 3.97 (s, 2H) ppm;
13C NMR (100 MHz, DMSO-d6) δ = 172.0 (less intense),
133.05 129.07, 128.97, 128.83, 125.59 (d, J = 232 Hz),
122.93 (d, J = 3 Hz), 115.27 (d, J = 20 Hz), 28.12 ppm;
MS (APCI): [M + 1]+ = 287.0 (99.2%); HRMS (ESI-
QTOF, [M + H]+): calculated for C15H12FN2OS: 287.0654;
found: 287.0650.
N-(2,4-dimethylphenyl)-4H-benzo[d][1,3]thiazin-2-
amine (6ac)[2f] (Scheme 5): Off-white solid; Rf = 0.45
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 231
mg (86%); m.p = 176.4-177.6 °C (Lit[2f] 176-177 °C); H
1
NMR (400 MHz, DMSO-d6) δ = 9.96 (br, 1H), 7.19-7.14
(m, 2H), 7.02 (d, J = 2.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H),
6.91 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.72 (br,
1H), 3.92 (s, 2H), 2.21 (s, 3H), 2.07 (S, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ = 152.48, 135.4, 130.37,
128.34, 127.16, 124.75, 122.3, 120.92, 28.78, 21.08, 17.94
ppm; MS (APCI): [M + 1]+ = 269.1 (98.10%); HRMS
(ESI-QTOF, [M + H]+): calculated for C16H17N2S:
269.1112; found: 269.1114.
N-(7-chloro-4H-benzo[d][1,3]thiazin-2-yl)benzamide
(6ea)[2f] (Scheme 4): White solid; Rf = 0.60 (SiO2,
EtOAc/Hexane = 8:2); purification system: CombiFlash
MPLC (EtOAc/Hexane = 20:80); yield: 266 mg (88%);
1
m.p = 152.2-153.4 °C (Lit[2f] 151-152 °C); H NMR (400
MHz, DMSO-d6) δ = 11.71 (br, 1H), 8.05 (d, J = 7.6 Hz,
2H), 7.57 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.29
(d, J = 8.4 Hz, 1H) 7.19 (br, 2H), 3.95 (s, 2H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ = 136.3 (less intense),
132.76, 132.57, 129.39, 128.97, 128.81, 124.9, 120.6,
27.65 ppm; MS (APCI): [M + 1]+ = 303.0 (99.80%);
N-(2-methoxyphenyl)-4H-benzo[d][1,3]thiazin-2-amine
(6ad)[2f] (Scheme 5): White solid; Rf = 0.60 (SiO2,
Hexane/EtOAc = 8:2); purification system: CombiFlash
MPLC (EtOAc /Hexane= 20:80); yield: 238 mg (88%);
HRMS (ESI-QTOF, [M
+
H]+): calculated for
1
m.p = 117.2-118.1 °C (Lit[2f] 116-118 °C); H NMR (400
C15H12ClN2OS: 303.0358; found: 303.0354.
MHz, DMSO-d6) δ = 9.15 (br, 1H), 7.46 (br, 1H), 7.21-
7.15 (m, 2H), 7.04-6.93 (m, 4H), 6.89-6.85 (dt, J = 8.0 Hz,
1H), 3.93 (s, 2H), 3.75 (s, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ = 152.1, 151.03, 128.35, 127.2, 124.34,
123.23, 122.87, 120.91, 120.7, 111.82, 55.92, 28.9 ppm;
MS (APCI): [M + 1]+ = 271.1 (98%); HRMS (ESI-QTOF,
[M + H]+): calculated for C15H15N2OS: 271.0905; found:
271.0908.
N-(7-(trifluoromethyl)-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (6fa)[2f] (Scheme 4): White solid; Rf = 0.50
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 296
mg (88%); m.p = 116.6-117.8 °C (Lit[2f] 116-117 °C); H
1
NMR (400 MHz, DMSO-d6) δ = 11.84 (br, 1H), 8.05 (d, J
= 7.2 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.51-7.45 (m, 5H),
4.05 (s, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ =
134.8 (less intense), 132.84, 129.72, 129.3, 129.2 (q, J =
31.8 Hz), 128.5, 126.12, 124.38 (q, J = 271 Hz), 121.7,
27.94 ppm; MS (APCI): [M + 1]+ = 337.0 (98.57%);
Ethyl(4H-benzo[d][1,3]thiazin-2-yl)carbamate (6ah)[2f]
(Scheme 5): White solid; Rf = 0.60 (SiO2, Hexane/EtOAc
=
8:2); purification system: CombiFlash MPLC
(Hexane/EtOAc = 90:10); yield: 208 mg (88%); m.p = 92-
93 °C (Lit[2f] 93-94 °C); 1H NMR (400 MHz, DMSO-d6) δ
= 11.10 (br, 1H), 7.25-7.19 (m, 2H), 7.10-7.04 (m, 2H),
4.06 (q, J = 7.8 Hz, 2H), 3.94 (s, 2H), 1.18 (t, J = 8.0 Hz,
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 157.6 (less
intense), 139.98, 128.52, 127.27, 125.1, 120.88, 61.28,
28.07, 14.84 ppm; HRMS (ESI-QTOF, [M + H]+):
calculated for C11H13N2O2S: 237.0697; found: 237.0694.
HRMS (ESI-QTOF, [M
+
H]+): calculated for
C16H12F3N2OS: 337.0622; found: 337.0618.
N-(4-phenyl-4H-benzo[d][1,3]thiazin-2-yl)benzamide
(6ga) (Scheme 4): Off-White solid; Rf = 0.50 (SiO ,
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 80:20); yield: 258 mg (75%);
1
m.p = 87.0-88.0 °C; H NMR (400 MHz, DMSO-d6) δ =
(6ai)[2f]
11.65 (br, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 7.2
Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.38-7.28 (m, 4H), 7.25-
7.09 (m, 5H), 5.57 (s, 1H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ = 171.1, 141.37, 134.98, 132.68, 131.32,
129.19, 128.96, 128.77, 128.06, 127.86, 127.66, 125.88,
N-phenyl-4H-benzo[d][1,3]thiazin-2-amine
(Scheme 5): Off-White solid; Rf
=
0.60 (SiO2,
Hexane/EtOAc = 8:2); purification system: CombiFlash
MPLC (Hexane/EtOAc = 85:15); yield: 221 mg (92%);
m.p = 202.2 – 203.4 °C (Lit[2f] 201-202 °C); H NMR
1
(400 MHz, DMSO-d6) δ = 9.43 (br, 1H), 7.84 (br, 2H),
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001149
Advanced Synthesis & Catalysis
7.27 (t, J = 8.0 Hz, 2H), 7.23-7.16 (m, 2H), 7.06-6.96 (m,
3H), 4.00 (s, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
= 152.0 (less intense), 142.9 (less intense), 129.0, 128.37,
127.26, 124.69, 123.92, 122.78, 120.77, 120.09, 29.11
ppm; MS (APCI): [M + 1]+ = 241.1 (98.2%); HRMS (ESI-
QTOF, [M + H]+): calculated for C14H13N2S: 241.0799;
found: 241.0796.
42.58, 33.31, 30.18, 27.46 ppm; MS (APCI): [M + 1]+ =
247.1 (99.00%); HRMS (ESI-QTOF, [M
+
H]+):
calculated for C13H15N2OS: 247.0905; found: 247.0901.
(E)-N-(tetrahydropyrrolo[1,2-c]thiazol-3(1H)-
ylidene)aniline (8ai) (Scheme 6): White solid; Rf = 0.4
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 192
1
N-(o-tolyl)-4H-benzo[d][1,3]thiazin-2-amine
(Scheme 5): White solid; Rf = 0.60 (SiO2, EtOAc/Hexane
(6aj)[2f]
mg (88%); m.p = 101.0-102.2 °C; H NMR (400 MHz,
DMSO-d6) δ = 7.27 (t, J = 7.6 Hz, 2H), 7.01 (t, J = 7.6 Hz,
1H), 6.84 (d, J = 7.6 Hz, 1H), 4.27-4.19 (m, 1H), 3.61-3.54
(m, 1H), 3.42-3.35 (m, 1H), 3.29-3.23 (m, 1H), 3.05 (t, J =
8.4 Hz, 1H), 2.25-2.00 (m, 3H), 1.65-1.55 (m, 1H) ppm;
13C NMR (100 MHz, DMSO-d6) δ = 156.33, 129.15,
122.78, 122.00, 64.65, 45.85, 33.44, 30.41, 27.58 ppm;
HRMS (ESI-QTOF, [M + H]+): calculated for C12H15N2S:
219.0955; found: 219.0952.
=
8:2); purification system: CombiFlash MPLC
(Hexane/EtOAc = 85:15); yield: 234 mg (92%); m.p =
168.8-169.8 °C (Lit[2f] 168-169 °C); H NMR (400 MHz,
1
DMSO-d6) δ = 10.00 (br, 1H), 7.19-7.15 (m, 3H), 7.09 (t, J
= 8.0 Hz, 1H), 7.00-6.90 (m, 4H), 3.93 (s, 2H), 2.13 (s,
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 152.53,
130.52, 128.35, 127.17, 126.45, 124.04, 122.32, 120.93,
28.77, 18.37 ppm; MS (APCI): [M + 1]+ = 254.82
(99.20%); HRMS (ESI-QTOF, [M + H]+): calculated for
C15H15N2S: 255.0955; found: 255.0954.
(E)-N-(tetrahydro-1H-thiazolo[3,4-a]pyridin-3(5H)-
ylidene)aniline (8ba) (Scheme 6): White solid; Rf = 0.6
(SiO2, Hexane/EtOAc
= 8:2); purification system:
N-(4-methoxyphenyl)-4H-benzo[d][1,3]thiazin-2-amine
(6ak)[2f] (Scheme 5): Pinkish solid; Rf = 0.55 (SiO ,
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 85:15); yield: 251 mg (93%);
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 218
1
mg (84%); m.p = 116.2-117.4 °C; H NMR (400 MHz,
CDCl3)) δ = 8.26 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 8.0 Hz,
1H), 7.40 (t, J = 8.0 Hz, 2H), 4.82 (dd, J = 8.6 Hz, 1H),
4.65 (ddd, J = 8.4 Hz, 1H), 4.29 (dd, J = 8.1 Hz, 1H), 2.82
(t, J = 7.9 Hz, 1H), 2.01-1.96 (m, 2H), 1.81 (d, J = 8.1 Hz,
1H),), 1.56-1.46 (m, 3H), 1.26 (d, J = 9.2 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ = 175.94, 172.05, 136.85,
131.68, 129.53, 127.9, 60.24, 46.3, 33.48, 32.1, 24.3, 23.87
ppm; HRMS (ESI-QTOF, [M + H]+): calculated for
C14H17N2OS: 261.1061; found: 261.1055.
1
m.p = 179.6-180.8 °C (Lit[2f] 170-180 °C); H NMR (400
MHz, DMSO-d6) δ = 9.29 (br, 1H), 7.74 (br, 2H), 7.21-
7.14 (m, 2H), 7.01-6.99 (m, 2H), 6.86 (dd, J = 8.2 Hz, 2H),
3.98 (s, 2H), 3.71 (s, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ = 155.19, 150.2 (less intense), 145.2 (less
intense), 128.32, 127.22, 121.84, 120.79, 114.18, 55.61,
29.13 ppm; MS (APCI): [M + 1]+ = 271.1 (99.20%);
HRMS (ESI-QTOF, [M
+
H]+): calculated for
C15H15N2OS: 271.0905; found: 271.0904.
(E)-3-(phenylimino)hexahydro-1H-thiazolo[3,4-
a]pyridin-1-one (8ci) (Scheme 6): White solid; Rf = 0.4
N-(pyridin-3-yl)-4H-benzo[d][1,3]thiazin-2-amine
(6al)[2f] (Scheme 5): Brown solid; Rf = 0.2 (SiO2,
Hexane/EtOAc = 8:2); purification system: CombiFlash
MPLC (Hexane/EtOAc = 70:30); yield: 202 mg (84%);
(SiO2, Hexane/EtOAc = 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 231
1
mg (94%); m.p = 155.4-156.2 °C; H NMR (400 MHz,
DMSO-d6) δ = 7.52-7.42 (m, 3H), 7.34-7.30 (m, 2H), 4.67
(dd, J = 9.1, 4.4 Hz, 1H), 4.39 (dd, J = 11.4, 4.2 Hz, 1H),
3.15 (dt, J = 12.9, 3.2 Hz, 1H), 2.16-2.11 (m, 1H), 1.95-
1.80 (m, 2H), 1.69-1.52 (m, 2H), 1.43 (ddd, J = 16.3, 12.7,
6.3 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ =
179.04, 173.55, 134.20, 129.34, 129.14, 129.05, 60.34,
43.85, 27.78, 25.14, 22.59 ppm; MS (APCI): [M + 1]+ =
1
m.p = 146.2-147.4 °C (Lit[2f] 145-146 °C); H NMR (400
MHz, DMSO-d6) δ = 9.67 (br, 1H), 8.94 (br, 1H), 8.34 (br,
1H), 8.19 (d, J = 7.6 Hz, 1H), 7.32-7.30 (m, 1H), 7.26-7.18
(m, 2H), 7.07-7.0 (m, 2H), 4.04 (s, 2H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ = 150.8 (less intense), 143.63,
141.59, 128.48, 127.32, 124.45, 123.88, 120.71, 29.02
ppm; MS (APCI): [M + 1]+ = 242.10 (99.85%); HRMS
(ESI-QTOF, [M + H]+): calculated for C13H12N3S:
242.0751; found: 242.0747.
247.1 (99.08%); HRMS (ESI-QTOF, [M
+
H]+):
calculated for C13H15N2OS: 247.0905; found: 247.0901.
Analytical Data of Synthesized N,S-spirocycles 10aa-da
Ethyl
3-((4H-benzo[d][1,3]thiazin-2-
yl)amino)propanoate (6am)[2f] (Scheme 5): White solid;
Rf = 0.60 (SiO , Hexane/EtOAc = 8:2); purification
system: CombiF2lash MPLC (Hexane/EtOAc = 80:20);
yield: 224 mg (85%); m.p = 60-61 °C (Lit[2f] 59-60 °C);
1H NMR (400 MHz, DMSO-d6) δ = 7.36 (br, 1H), 7.16-
7.08 (m, 2H), 6.91 (t, J = 8.0 Hz, 2H), 4.05 (q, J = 7.6 Hz,
2H), 3.87 (s, 2H), 3.55 (t, J = 6.8 Hz, 2H), 2.60 (t, J = 7.8
Hz, 2H), 1.16 (t, J = 8.0 Hz, 3H) ppm; 13C NMR (100
MHz, DMSO-d6) δ = 171.78, 153.27, 146.31, 128.21,
127.1, 124.22, 122.82, 120.62, 60.34, 38.16, 34.12, 29.04,
14.53 ppm; MS (APCI): [M + 1]+ = 265.1 (99.20%);
N-(7-oxo-6-thia-4-azaspiro[2.4]hept-4-en-5-
yl)benzamide (10aa) (Scheme 7): White solid; Rf = 0.4
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 172
1
mg (70%); m.p = 143.2-144.4 °C; H NMR (400 MHz,
DMSO-d6) δ = 12.19 (br, 1H), 8.00 (d, J = 7.6 Hz, 2H),
7.62 (t, J = 7.0 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 1.77 (d, J
= 3.2 Hz, 2H), 1.64 (d, J = 4.0 Hz, 2H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ = 181.97, 168.96, 168.30, 133.47,
132.50, 129.0, 128.85, 57.30, 21.51, 15.85 ppm; HRMS
(ESI-QTOF, [M + H]+): calculated for C12H11N2O2S:
247.0541; found: 247.0543.
HRMS (ESI-QTOF, [M
C13H17N2O2S: 265.1010; found: 265.1003.
+
H]+): calculated for
N-(8-oxo-7-thia-5-azaspiro[3.4]oct-5-en-6-yl)benzamide
(10ba) (Scheme 7): Brown sticky liquid; Rf = 0.45 (SiO ,
Hexane/EtOAc = 8:2); purification system: CombiFlas2h
MPLC (Hexane/EtOAc = 80:20); yield: 161 mg (62 %);
1H NMR (Keto form) (400 MHz, DMSO-d6) δ = 10.97 (br,
1H), 7.96 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.50
(t, J = 7.9 Hz, 2H), 2.73-2.63 (m, 2H), 2.32-2.24 (m, 2H),
1.97-1.89 (m, 2H) ppm; 13C NMR (Keto form) (100 MHz,
DMSO-d6) δ = 179.36, 173.46, 168.44, 133.31, 131.59,
Analytical Data of Synthesized Pyrrolo[1,2-c]thiazoles
(8aa and ai) and Thiazolo[3,4-a]pyridines (8ba and ci)
(E)-N-(tetrahydropyrrolo[1,2-c]thiazol-3(1H)-
ylidene)benzamide (8aa) (Scheme 6): Off- white solid;
Rf = 0.6 (SiO2, Hexane/EtOAc = 8:2); purification
system: CombiFlash MPLC (Hexane/EtOAc = 80:20);
1
yield: 229 mg (93%); m.p = 124.2-125.1 °C; H NMR
1
(400 MHz, DMSO-d6) δ = 8.10 (d, J = 7.8 Hz, 2H), 7.51 (t,
J = 7.6 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 4.31-4.22 (m,
1H), 3.70-3.63 (m, 1H), 3.42 (dt, J = 8.0 Hz, 1H), 3.30 (t, J
128.92, 128.82, 61.51, 31.31, 15.76 ppm; H NMR (Enol
form) (400 MHz, DMSO-d6) δ = 10.62 (br, 1H), 7.84 (d, J
= 6.8 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 7.9 Hz,
= 9.0 Hz, 1H), 3.01 (t, J = 11.2 Hz, 1H), 2.29-2.03 (m, 3H), 2H), 2.73-2.63 (m, 2H), 2.32-2.24 (m, 2H), 1.97-1.89 (m,
1.67-1.55 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
= 173.46, 167.08, 136.88, 132.2, 129.41, 128.54, 64.17,
2H) ppm; 13C NMR (Enol form) (100 MHz, DMSO-d6) δ
= 179.36, 173.46, 168.29, 134.72, 132.84, 128.59, 127.86,
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001149
Advanced Synthesis & Catalysis
61.51, 31.31, 15.76 ppm; MS (APCI): [M + 1]+ = 261.9
(98.18%); HRMS (ESI-QTOF, [M + H]+): calculated for
C13H13N2O2S: 261.0697; found: 261.0694.
Chem. Soc., Chem. Commun. 1977, 43-44; c) A.
Dondoni, A. Battaglia, P. Giorgianni, J. Org. Chem.
1980, 45, 3766-3773; d) Y. Nomura, T. Hayama, Y.
Takeuchi, S. Tomoda, Y. Kato, Bull. Chem. Soc. Jpn.
1984, 57, 1276-1278. e) P. Carisi, G. Mazzanti, P. Zani,
G. Barbaro, A. Battaglia, P. Giorgianni, J. Chem. Soc.,
Perkin Trans. 1 1987, 2647-2651; f) T. Nishio, J. Org.
Chem. 1997, 62, 1106-1111 g) T. Nishio, H. Sekiguchi,
Heterocycles 2002, 58, 203-212; h) P. Csomós, L.
Fodor, G. Bernáth, J. Sinkkonen, J. Salminen, K.
Wiinamäki, K. Pihlaja, Tetrahedron 2008, 64, 1002-
1011; i) V. T. Abaev, F. A. Tsiunchik, A. V. Butin, A.
V. Gutnov, J. Heterocycl. Chem. 2008, 45, 475-480; j)
C. Gimbert, A. Vallribera, Org. Lett. 2009, 11, 269-
271; k) M. T. Corbett, S. Caille, Synlett 2017, 28, 2845-
2850.
N-(4-oxo-3-thia-1-azaspiro[4.4]non-1-en-2-
yl)benzamide (10ca) (Scheme 7): brown sticky solid; Rf
= 0.4 (SiO2, Hexane/EtOAc = 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 203
1
mg (74%); m.p = 112.2-113.4 °C; H NMR (400 MHz,
DMSO-d6) δ = 12.10 (br, 1H), 8.03 (d, J = 7.2 Hz, 2H),
7.60 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 2.05-1.92
(m, 2H), 1.92-1.76 (m, 6H) ppm; MS (APCI): [M + 1]+ =
275.1 (94.86%); HRMS (ESI-QTOF, [M
+
H]+):
calculated for C14H15N2O2S: 275.0854; found: 275.0852.
N-(5'-oxo-5'H-spiro[adamantane-2,4'-thiazol]-2'-
yl)benzamide (10da) (Scheme 7): White solid; Rf = 0.4
(SiO2, Hexane/EtOAc
= 8:2); purification system:
CombiFlash MPLC (Hexane/EtOAc = 80:20); yield: 238
1
mg (70%); m.p = 96.3-97.4 °C; H NMR (400 MHz,
DMSO-d6) δ = 11.71 (br, 1H), 8.03 (d, J = 8.0 Hz, 2H),
7.60 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 7.9 Hz, 2H), 2.40 (dd,
J = 13.8 Hz, 4H), 1.86-1.50 (m, 10H) ppm; 13C NMR (100
MHz, DMSO-d6) δ = 172.24, 133.21, 129.06, 128.99,
128.83, 38.21, 34.89, 34.64, 30.99, 27.31, 26.06 ppm;
[2] a) A. Z. Halimehjani, Y. L. Nosood, Org. Lett. 2017,
19, 6748-6751; b) N. Vodnala, D. Kaldhi, S. Polina, V.
P. R. K. Putta, R. Gupta, S. C. P. Promily, R. K.
Linthoinganbi, V. Singh, Malakar, C. C. Tetrahedron
Lett. 2016, 57, 5695-5699; c) D. Kaldhi, N. Vodnala, R.
Gujjarappa, S. Nayak, V. Ravichandiran, S. Gupta, C.
K. Hazra, Malakar, C. C. Tetrahedron Lett. 2019, 60,
223-229; d) V. P. R. K. Putta, R. Gujjarappa, U. Tyagi,
P. P. Pujar, C. C. Malakar, Org. Biomol. Chem. 2019,
17, 2516-2528; e) N. N. Makhova, L. I. Belen’kii, G. A.
Gazieva, I. L. Dalinger, L. S. Konstantinova, V. V.
Kuznetsov, A. N. Kravchenko, M. M. Krayushkin, O.
A. Rakitin, A. M. Starosotnikov, L. L. Fershtat, S. A.
Shevelev, V. Z. Shirinian, V. N. Yarovenko, Russ.
Chem. Rev. 2020, 89, 55-124; f) V. P. R. K. Putta, N.
Vodnala, R. Gujjarappa, U. Tyagi, A. Garg, S. Gupta, P.
P. Pujar, C. C. Malakar, J. Org. Chem. 2020, 85, 380-
396.
HRMS (ESI-QTOF, [M
+
H]+): calculated for
C19H21N2O2S: 341.1323; found: 341.1320.
Analytical Data of Isolated Intermediates 3aa and 11a
2-(3-Benzoylthioureido)benzoic acid (3aa)[12] (Scheme
8): White solid; Rf = 0.15 (SiO2, Hexane/EtOAc = 6:4);
purification system: CombiFlash MPLC (DCM/MeOH =
1
98:2); yield: 285 mg (95%); H NMR (400 MHz, DMSO-
d6) δ = 13.36 (s, 1H), 13.17 (s, 1H), 11.56 (s, 1H), 8.17 (d,
J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 8.0
Hz, 1H), 7.69-7.61 (m, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.38
(t, J = 8.0 Hz, 1H) ppm; MS (APCI):[M + 1]+ = 301.1
(99.84%); HRMS (EI-QTOF, [M + H]+): calculated for
C15H13N2O3S: 301.0646; found: 301.0641.
[3]a) A. G. Hoechst, GB1214000A, 25 Nov, 1970; b) B. A.
Dreikorn, U.S. Patent 4,001,227 A, 22 Dec, 1975; c) S.
I. El-Desoky, E. M. Kandeel, A. H. Abd-el-Rahman, R.
R. Schmidt, J. Heterocycl. Chem. 1999, 36, 153-160; d)
J. Matysiak, Bioorg. Med. Chem. 2006, 14, 2613-2619;
e) J. Huang, Y. Yong, H. Lu, Y. ZhiGang, X. Fan, S.
Qi, Chin. Sci. Bull. 2013, 58, 717-723.
2-Amino-N,N-dimethylbenzamide (11a)[13] (Scheme 8):
White solid; Rf = 0.25 (SiO2, Hexane/EtOAc = 8:2);
purification system: CombiFlash MPLC (Hexane/EtOAc
1
= 80:20); yield: 125 mg (76%); H NMR (400 MHz,
DMSO-d6) δ = 7.05 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz,
1H), 6.67 (d, J = 8.0 Hz, 1H), 6.52 (t, J = 8.0 Hz, 1H), 5.11
(s, 2H), 2.44 (s, 6H) ppm; MS (APCI):[M + 1]+ = 165.1
(100%); HRMS (EI-QTOF, [M + H]+): calculated for
C9H13N2O: 165.1027; found: 165.1023.
[4] a) S. S. Pelosi, U.S. Patent 4,002,622 A, 30 Oct, 1975;
b) J. P. Rieu, J. F. Patoiseau, G. W. John, U.S. Patent
6,011,032 A, 4 Jan, 2000; c) Y. Su, Q. Guo, G. Wang,
CN1683349A, 28 Feb, 2005; d) M. Anzini, A. Giordani,
F. Makovec, WO2009040331A2, 2 April, 2009.
Acknowledgements
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R. Gonsalves, J. A. Paixão, A. M. Beja, M. R. Silva, L.
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C.C.M. thank Science and Engineering Research Board (SERB),
Govt. of India for financial support in the form of research grant
ECR/2016/000337 and CRG/2020/004509. CCM also
acknowledge Technical Education Quality Improvement Program,
Phase-III and NIT Manipur for financial and research support
under Minor Research Grant. S.P, V.P.R.K.P. and P.P.P. grateful
to CHRIST (Deemed to be University) for their valuable research
support. R.G. grateful to Ministry of Education, New Delhi for
fellowship support.
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11
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FULL PAPER
P(III)-Mediated
Cascade
C-N/C-S
Bond
Formation: An Efficient Protocol Towards the
Synthesis of N,S-Heterocycles and Spiro
Compounds
Adv. Synth. Catal. Year, Volume, Page – Page
Saibabu Polina,a V. P. Rama Kishore Putta,a
Raghuram Gujjarappa,b Virender Singh,c Prasad
Pralhad Pujar,a* and Chandi C. Malakarb*
12
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