Facile synthesis of derivatives of 1,1,3-Trioxo-2H,4H-pyrrolo[1,2-b][1,2,4, 6]thiatriazine: A new heterocyclic system

Article abstract of DOI:10.1002/hc.21123

We reported a facile and efficient methodology to synthesize derivatives of pyrrolo[1,2-b][1,2,4,6]thiatriazine (PTTD): a new bridgehead nitrogen heterocyclic system. Treatment of methyl pyrrole-2-carboxylate with N-benzylsulfamoyl chlorides followed by subsequent hydrolysis reaction afforded 1-benzylsulfamoyl-1H-pyrrole-2-carboxylic acids, which underwent ring-closing reaction by treatment with diphenyl phosphorazidate via Curtius rearrangement; subsequent alkylation reaction afforded the desired 2,4-disubstituted-1,1,3- trioxo-2H,4H-PTTDs.

Full text of DOI:10.1002/hc.21123

Heteroatom Chemistry
Volume 24, Number 6, 2013
Facile Synthesis of Derivatives of 1,1,3-Trioxo-
2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine:
A New Heterocyclic System
Wenmin Chen, Peng Zhan, Diwakar Rai, Boshi Huang, Jiapei Yang,
and Xinyong Liu
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products
(Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West
Culture Road, 250012, Jinan, Shandong, People’s Republic of China
Received 5 July 2013; revised 6 September 2013
INTRODUCTION
ABSTRACT: We reported a facile and efficient
methodology to synthesize derivatives of pyrrolo
[1,2-b][1,2,4,6]thiatriazine (PTTD): a new bridgehead
nitrogen heterocyclic system. Treatment of methyl
pyrrole-2-carboxylate with N-benzylsulfamoyl chlo-
rides followed by subsequent hydrolysis reaction
afforded 1-benzylsulfamoyl-1H-pyrrole-2-carboxylic
acids, which underwent ring-closing reaction by
treatment with diphenyl phosphorazidate via Cur-
tius rearrangement; subsequent alkylation reaction
afforded the desired 2,4-disubstituted-1,1,3-trioxo-
Heterocyclic compounds that constitute the
largest important class of organic chemistry are
significantly important in synthetic chemistry
because of their broad pharmacological applica-
tions. Therefore, synthetic chemists have been
engaged in extensive efforts to explore novel het-
erocyclic compounds with biological activities.
Recently, there has been a great interest in het-
erothiadiazines because of their diverse antiviral
activities against human cytomegalovirus, varicella
zoster virus, hepatitis C virus, and human immun-
odeficiency virus (HIV) [1]. Among them, a class
of 2,4-disubstitued-1,1,3-trioxo-2H,4H-thieno[3,4-
e][1,2,4]thiadiazines (TTDs) (Fig. 1) was reported as
potent HIV-1 non-nucleoside reverse transcriptase
inhibitors (NNRTIs) [2]. Structure-activity relation-
ship studies of TTDs demonstrated that the dual
substitutions at N-2 and N-4 positions of 1,2,4-TTD
ring were necessary for their antiviral activities
[3]. In an effort to explore bioisosteres of TTDs,
we have synthesized three classes of heterothiadi-
azine derivatives: thieno[2,3-e][2,1,3]thiadiazines
(TTDDs) [4], pyrazolo[4,5-e][2,1,3]thiadiazines
(PTDDs) and pyrazolo[4,5-e][1,2,4]thiadiazines
(PTDs) [5], which also displayed potential activities
against HIV-1. As a continuation of our research,
we constructed a new bridgehead nitrogen hetero-
cyclic system, viz. 1,1,3-trioxo-2H,4H-pyrrolo[1,2-
b][1,2,4,6]thiatriazine (PTTD) as the bioisostere of
TTD (Fig. 1).
ꢀC
2H,4H-PTTDs.
2013 Wiley Periodicals, Inc.
Heteroatom Chem. 24:495–501, 2013; View this
article online at wileyonlinelibrary.com. DOI
10.1002/hc.21123
Correspondence to: Xinyong Liu; e-mail: xinyongl@sdu.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 81273354, 81102320, 30873133,
30772629, and 30371686.
Contract grant sponsor: Key Project of NSFC for International
Cooperation.
Contract grant number: 30910103908.
Contract grant sponsor: Research Fund for the Doctoral Pro-
gram of Higher Education of China.
Contract grant number: 20110131130005.
Contract grant sponsor: Shandong Provincial Natural Science
Foundation.
Contract grant number: ZR2009CM016.
2013 Wiley Periodicals, Inc.
ꢀC
495

496 Chen et al.
FIGURE 1 Structures of TTDs and PTTDs.
Toluene
Toluene
However, to the best of our knowledge, no syn-
thetic method is yet available in the literature on
this unique heterobicyclic ring system. In our pre-
vious studies, we have developed a methodology
for preparing PTD by intramolecular cyclization of
carboxylic acids with amino groups in the same
molecules via Curtius rearrangement [5, 6]. It was
envisioned that this methodology would allow for
the synthesis of a range of a structurally diverse het-
erobicyclic ring system. So we decided to extend our
method to synthesize PTTD. However, this classical
Curtius reaction has considerable limitations, such
as utilization of the toxic sodium azide or hydrazine
as azide reagent [7] and isolation of potentially ex-
plosive acyl azide intermediates. Therefore, we de-
cided to apply the safe diphenyl phosphorazidate
(DPPA) [8] as the azide-transfer reagent. Herein,
we report a facile and efficient methodology for the
synthesis of 1,2,4,6-PTTDs, with convenient DPPA-
modified Curtius reaction [9] as the key step.
SCHEME 1 Synthetic route of PTTDs by strategy 1.
tected the N-Boc group of 2 utilizing trifluoroacetic
acid to give sulfamoyl-1H-pyrrole-2-carboxylic acid
(3, 95%), which would serve as a substrate for
the Curtius reaction. However, the subsequent ring-
closing reaction of 3 using DPPA and triethylamine
in toluene at 65◦C for 12 h led to the formation of
1,1,3-trioxo-2H-pyrrolo[1,2-b][1, 2, 5]thiadiazole (4)
(yield 62%), rather than the expected PTTD ring (5)
(Scheme 1).
We assumed that the acyl azide intermediate
3a formed by the treatment of 3 with DPPA read-
ily underwent an intramolecular nucleophilic attack
of amino on the active carbonyl carbon to produce
the cyclization product 4 without rearrangement
(Scheme 1). The expected Curtius rearrangement re-
action didn’t occur even under higher temperature
(80◦C) and longer time (24 h). The nucleophilicity of
sulfamoyl group and its favorable steric position for
intramolecular reaction may be responsible for the
high tendency of intramolecular nucleophilic reac-
tion rather than rearrangement reaction in this case.
After the failure of the first synthetic strategy,
we turned our attention to another alternative strat-
egy, which was to join a steric N-2 benzyl group
before the formation of PTTD ring (Scheme 2,
strategy 2). This synthetic strategy makes use
of 1-benzylsulfamoyl-1H-pyrrole-2-carboxylic acids
(7a,b) as the intermediate. The starting material
RESULTS AND DISCUSSION
In our efforts to prepare the desired PTTD deriva-
tives, two synthetic strategies were attempted. In-
spired by the reported synthetic approach for PTD
[10], our initial plan was to prepare a PTTD ring
(5) which subsequently underwent regioselective N-
alkylation at N-2 and N-4 positions, respectively, to
give the target PTTDs (strategy 1, Scheme 1). The
second strategy, which ultimately proved to be suc-
cessful, was to join N-2 benzyl group before the for-
mation of PTTD ring (strategy 2, Scheme 2). The un-
successful former approach will be discussed first,
which shed light on some of the unique chemistry of
PTTD (5).
According to the first strategy, we first synthe-
sized the key intermediate 1-(N-Boc-sulfamoyl)-1H-
pyrrole-2-carboxylic acid (2) by treatment of methyl
pyrrole-2-carboxylate with N-Boc-sulfamoyl chlo-
ride (1) in the presence of sodium hydride, fol-
lowed by hydrolysis reaction in one pot in high
yield (85%). Subsequently, treatment of 2 with DPPA
generated no cyclization product. As an alternative
approach to prepare PTTD ring, we then depro-
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of Derivatives of 1,1,3-Trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine 497
SCHEME 2 Synthetic route of PTTDs (9–21) by strategy 2.
N-benzylsulfamoyl chlorides 6 (a,b) were synthe-
sized from commercially available benzylamines by
the reported method [4]. The synthesis of 2-benzyl-
1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1, 2, 4, 6]thiatri-
azine (8a) was taken as a model reaction. Methyl
pyrrole-2-carboxylate (1.0 equivalent) was treated
with 6a (1.2 equiv) in the presence of excessive
sodium hydride (3.0 equiv), followed by a subse-
quent hydrolysis reaction in one pot to provide 1-
benzylsulfamoyl-1H-pyrrole-2-carboxylic acid 7a in
the yield of 82%. Subsequent ring-closing reaction
of 7a by treatment of DPPA (1.2 equiv) and triethy-
lamine (1.2 equiv) via Curtius rearrangement at 70◦C
afforded 8a in a yield of 58%.
was done via intramolecular electrophilic attack to
form the heterobicyclic ring system 8a. The steric
hindrance of the internal benzylamine nucleophile
in intermediate IV may limit the yields of pyrroloth-
iatriazines 8a (58%).
With the optimized synthetic conditions
in hand, 2-(4-methylbenzyl)-1,1,3-trioxo-2H,4H-
pyrrolo[1,2-b][1,2,4,6]thiatriazine 8b was also
prepared according to the obtained synthetic route
starting from 4-methylbenzylsulfamoyl chloride 6b
(Scheme 2).
After obtaining 8 (a,b), we further substituted at
N-4 position of PTTD ring with different benzyl, al-
lyl, and alkyl halides or α-haloesters in the presence
of sodium hydride to provide the desired PTTD com-
pounds 9–21 (Scheme 2, Table 1). As shown in the
Table 1, this method has the ability to tolerate a wide
variety of substitutions in moderate to good yield
(65%–85%). All the synthesized compounds were ad-
equately characterized by the physical and spectral
data.
The obtained (8a) was characterized by 1H-
nuclear magnetic resonance (NMR), 13C-NMR, high
resolution mass spectrometry (HRMS), and infrared
(IR) spectroscopy, which support its structural fea-
tures. One triplet at δ 6.42 and two double doublets
at δ 5.66 and 7.13 in 1H-NMR spectrum were at-
tributable to the pyrrole protons. The carbonyl car-
bon ( C O) signal at δ 147.9 and the N H proton
signal at δ 11.92 together with the corresponding in-
frared peaks at 3124 and 1707 cm−l indicated the
presence of CONH group in 8a.
A plausible reaction mechanism for the synthe-
sis of ring (8a) via ring-closing reaction using DPPA
is depicted in Scheme 3 [9]. The carboxylate anion of
7a attacked the phosphorus atom of DPPA and gen-
erated the acyl phosphates I and II, which respec-
tively underwent SN2-type reaction and SNi-type re-
arrangement with azide anion to form the acyl azide
III. In the next step, the acyl azides III would ther-
mally undergo the Curtius rearrangement to give the
isocyanates IV. Then cyclization of intermediate IV
CONCLUSIONS
In summary, we have developed a facile and efficient
synthetic procedure for the preparation of deriva-
tives of 1,2,4,6-PTTDs (9–21) using DPPA-mediated
Curtius rearrangement as the key step. This mod-
ified Curtius reaction was performed using one-
pot procedure without separating the explosive acyl
azide intermedate; it was much simpler and less la-
borious than the classical Curtius reaction [8, 11].
Additionally, this new heterobicyclic ring system will
serve as a new building block in medicinal and syn-
thetic chemistry, and our further investigation on
Heteroatom Chemistry DOI 10.1002/hc

498 Chen et al.
SCHEME 3 A plausible reaction mechanism for the synthesis of 8a.
TABLE 1 Synthesis of PTTDs (9–21)a
in hertz (Hz). Melting points (mp) were determined
on a micromelting point apparatus (Tian Jin Ana-
lytical Instrument Factory, Nankai, Tianjin, China).
Flash column chromatography was performed
on columns packed with silica gel 60 (200–300
mesh) (Qingdao waves silica gel desiccant co., Ltd,
Qingdao, China). Thin layer chromatography was
Yield b
Product (%)
Entry Substrate
R2X
1
2
3
4
5
6
7
8
9
10
11
12
13
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8b
8b
8b
4-Chlorobenzyl chloride
3-Bromobenzyl chloride
3-Fluorobenzyl chloride
Ethyl bromoacetate
Methyl iodide
Bromoethane
4-Methylbenzyl chloride
Cinnamyl chloride
9
82
70
75
82
75
67
75
78
65
85
78
72
80
10
11
12
13
14
15
16
17
18
19
20
21
ꢀR
performed on pre-coated HUANGHAI HSGF254,
0.15-0.2 mm TLC-plates (Yantai Jiangyou Silica Gel
Development Co., Ltd., Yantai, Shandong, China).
Solvents (Tianjin Fuyu Fine Chemical Co., Ltd.,
Wuqing, Tianjin, China) were of reagent grade
and were purified and dried by standard methods
when necessary. The key reactants including methyl
1H-pyrrole-2-carboxylate, benzylamines, benzyl
halides, alkyl halides, and DPPA were purchased
from Adamas-beta Co. Ltd (Shanghai, China).
Allyl bromide
4-Chlorobenzyl chloride
3-Fluorobenzyl chloride
4-Methyoxybenzyl chloride
4-Methylbenzyl chloride
aConditions: 8 (a,b) (1 mmol, 1.0 equiv), R2X (1.2 mmol, 1.2 equiv),
sodium hydride (60% in mineral oil, 1.2 mmol, 1.2 equiv), DMF (5 mL),
75◦C, 12 h.
bIsolated yields after column chromatography.
1-(N-Boc-sulfamoyl)-1H-pyrrole-2-carboxylic
acid 2. Methyl 1H-pyrrole-2-carboxylate (125 mg,
1.0 mmol, 1.0 equiv) was added to a stirring sus-
pension of sodium hydride (60% in mineral oil)
(80 mg, 2.0 mmol, 2.0 equiv) in 10 mL of anhydrous
tetrahydrofuran (THF). The reaction mixture was
stirred at 0◦C for 30 min, and then a solution of
N-Boc-sulfamoyl chloride (1) (1.5 mmol, 1.0 equiv,
prepared in our lab) in anhydrous THF was drop-
wise added. After the completion of reaction,
water was cautiously added to quench the reaction
followed by the addition of 2N aq. LiOH solution
(5 mL). The mixture solution was stirred at room
temperature for 6 h. Then the organic solvent was
removed under reduced pressure and the aqueous
layer was acidified with concentrated hydrochloric
acid to adjust to pH 1. The resulting precipitate
was filtered off and subsequently purified by flash
column chromatography to give the intermediate 2
as a white powder (85%), decomposed at 190–192◦C.
1H-NMR (600 MHz, CDCl3) δ ppm: 1.32 (s, 9H), 6.32
the exploration of novel bioactive compounds con-
taining PTTD scaffold is underway.
Experimental
Mass spectrometry was performed on an API 4000
triple-quadrupole mass spectrometer (Applied
Biosystems/MDS Sciex, Concord, ON, Canada). IR
spectra were recorded with Nicolet-6700 model
FT-IR spectrometer (Thermo Scientific, Waltham,
MA, USA) using KBr pellets. 1H-NMR and 13C-NMR
spectra were recorded on a Bruker Avance DRX
600 spectrometer (Bruker, Fa¨llanden, Switzerland),
Bruker AV-400 spectrometer (Bruker BioSpin,
Switzerland), or Bruker AVANCE-300 spectrometer
(Bruker BioSpin, Switzerland), using solvents as
indicated (CDCl3 or DMSO-d6). Chemical shifts were
reported in δ values (ppm) with tetramethylsilane
as the internal reference, and J values were reported
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of Derivatives of 1,1,3-Trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine 499
(t, J = 3.0 Hz, 1H), 7.07 (t, J = 1.8 Hz, 1H), 7.51 (s,
ganic solvent was removed under reduced pressure
and the remaining aqueous solution was acidified
with concentrated hydrochloric acid to adjust to pH
1. The resulting precipitate was filtered off and pu-
rified by column chromatography using ethyl ac-
etate/petroleum ether as eluent to give intermediate
1H), 12.61 (s, 2H); 13C-NMR (125 MHz, DMSO-d6)
δ ppm: 27.87, 83.34, 109.71, 123.11, 125.30, 131.63,
149.37, 159.90; ESI-MS: 308.4 [M+NH4]+, 313.3
[M+Na]+.
1
1-Sulfamoyl-1H-pyrrole-2-carboxylic acid 3. 1-
(N-Boc-sulfamoyl)-1H-pyrrole-2-carboxylic acid 2
(290 mg, 1.0 mmol, 1.0 equiv) and trifluoroacetic
acid (1142 mg, 10 mmol, 10 equiv) was dissolved
in 2 mL of dichloromethane, and stirred for 6 h at
room temperature. Then the dichloromethane layer
was removed under reduced pressure. The water
was added to the remaining liquid and resulting
precipitate was filtered off, and was purified by re-
crystallization using a mixture of petroleum ether
and ethyl acetate to give intermediate 3 as a white
7a as a white solid (82%): mp: 124–126◦C. H-NMR
(300 MHz, DMSO-d6) δ ppm: 4.21 (s, 2H, CH2), 6.18
(t, J = 3.3 Hz, 1H), 6.92 (dd, J = 3.6 Hz, J = 1.8 Hz,
1H), 7.17–7.25 (m, 5H), 7.32 (dd, J = 3.0 Hz, 1.8 Hz,
1H), 8.31 (s, 1H, NH), 12.84 (brs, 1H, OH); 13C-NMR
(75 MHz, DMSO-d6) δ ppm: 47.5, 161.2, 109.4, 122.6,
122.4, 127.9, 128.1, 128.7, 129.7, 136.7; ESI-MS:
281.5 [M+H]+, 303.5 [M+Na]+, 298.7 [M+NH4]+.
1-(4-methylbenzyl)sulfamoyl-1H-pyrrole-2-carb
oxylic acid (7b): White solid (80% yield): mp:
135–137◦C; ESI-MS: 295.2 [M+H]+.
1
powder (95%), decomposed at 194–196◦C. H-NMR
(400 MHz, CDCl3) δ ppm: 6.25 (t, J = 3.3 Hz, 1H),
7.04 (dd, J = 3.3 Hz, 1.6 Hz, 1H), 7.48 (d, J = 2.0 Hz,
1H), 8.08 (s, 2H); 13C-NMR (125 MHz, DMSO-d6) δ
ppm: 109.00, 122.37, 124.18, 128.82, 161.61; ESI-
MS: 189.3 [M–H]−; HRMS: C5H5N2O4S [M–H]−,
found 188.9986, calcd 188.9976.
General procedure for the preparation of 2-ben-
zyl-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatria-
zines 8 (a,b). Triethylamine (121 mg, 1.2 mmol, 1.2
equiv) was added to a solution of 7(a,b) (1.0 mmol,
1.0 equiv) and DPPA (332 mg, 1.2 mmol, 1.0 equiv)
in 100 mL of dry toluene. The reaction mixture was
stirred at 70◦C for 12 h. The solvent was evaporated
and the residue was purified by flash column chro-
matography using ethyl acetate/petroleum ether as
eluent to yield 8 (a,b).
1,1,3-Trioxo-2H-pyrrolo[1,2-b][1,2,5]thiadiazole
4. Triethylamine (12 mg, 1.2 mmol, 1.2 equiv)
was added to a solution of intermediate 3 (190 mg,
1 mmol, 1.0 equiv) and DPPA (332 mg, 1.2 mmol,
1.2 equiv) in 100 mL of dry toluene. The reaction
mixture was stirred at 70◦C for 12 h. The solvent was
evaporated under reduced pressure and the residue
was purified by flash column chromatography using
ethyl acetate/petroleum ether as eluent to yield
1,1,3-trioxo-2H-pyrrolo[1,2-b][1,2,5]thiadiazole (4)
as a white powder (62%), decomposed at 198–200◦C.
1H-NMR (600 MHz, DMSO-d6) δ ppm: 6.22 (s, 1H),
6.29 (s, 1H), 7.19 (s, 1H); 13C-NMR (100 MHz,
DMSO-d6) δ ppm: 103.61, 116.14, 116.60, 134.34,
162.17; ESI-MS: 171.1 [M–H]−; HRMS: C5H3N2O3S
[M–H]−, found 170.9886, calcd 170.9870.
2-Benzyl-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,
6]thiatriazine 8a. White solid (58%): mp: 128–
1
130◦C. H-NMR (300 MHz, DMSO-d6) δ ppm: 5.02
(s, 2H), 5.66 (dd, J = 3.6 Hz, 1.5 Hz, 1H), 6.42 (t,
J = 3.4 Hz, 1H), 7.13 (dd, J = 3.3 Hz, 1.5 Hz, 1H),
7.27–7.38 (m, 5H), 11.92 (s, 1H); 13C-NMR (75 MHz,
DMSO-d6) δ ppm: 45.90, 93.25, 110.82, 114.43,
136.35, 128.34, 128.85, 128.42, 129.01, 147.92; ESI-
MS: 278.3 [M+H]+; HRMS: C12H12N3O3S [M+H]+,
found 278.0437, calcd 278.0594.
2-(4-Methylbenzyl)-1,1,3-trioxo-2H,4H-pyrrolo[1,
2-b][1,2,4,6]thiatriazine 8b. White solid (55%
yield): mp: 120–122◦C. 1H-NMR (400 MHz, CDCl3) δ
ppm: 2.50 (s, 3H), 4.97 (s, 2H), 5.65 (dd, J = 3.4 Hz,
1.5 Hz, 1H), 6.40 (t, J = 3.4 Hz, 1H), 7.11 (dd, J =
3.4 Hz, 1.6 Hz, 1H), 7.13–7.26 (m, 5H), 11.85 (s,
1H); 13C-NMR (100 MHz, DMSO-d6) δ ppm: 45.80,
93.10, 110.70, 114.36, 128.17, 128.40 (2C), 129.21,
129.55 (2C), 133.26, 137.69, 147.89; ESI-MS: 291.3
[M+H]+; HRMS: C13H14N3O3S [M+H]+, found
292.0658, calcd 292.0750.
1-Benzylsulfamoyl-1H-pyrrole-2-carboxylic acid
7 (a,b). Methyl pyrrole-2-carboxylate (125 mg,
1.0 mmol, 1.0 equiv) was added to a stirring suspen-
sion of sodium hydride (60% in mineral oil) (129 mg,
3.0 mmol, 3.0 equiv) in 5 mL of anhydrous THF. The
reaction mixture was stirred at 0◦C for 30 min, and
then a solution of N-benzylsulfamoyl chloride (6a)
(2 mmol, 2.0 equiv, prepared in our lab) in anhy-
drous THF was dropwise added. After completion of
the reaction, water was cautiously added to quench
the reaction followed by the addition of 2 mL of
5N aq. NaOH solution. The mixture solution was
stirred at room temperature for 12 h. Then the or-
General procedure for the preparation of 2,4-
disubstitued-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,
6]thiatriazines 9–21 (Scheme 2, Table 1). Sodium
Heteroatom Chemistry DOI 10.1002/hc

500 Chen et al.
hydride (57.6 mg, 2.4 mmol) was added to a solution
of 8 (a,b) (2.0 mmol) in dry DMF (10 mL) at 0◦C.
After stirring for 15 min, the corresponding alkyl
halide (2.4 mmol) was added. The resulting mixture
was stirred at 75◦C for 12 h. Then the solvent
was evaporated in vacuum and the residue was
purified by flash column chromatography using
dichloromethane/petroleum ether as an eluent to
give 9–21.
Compound 13 (Table 1, entry 5). White solid
(75% yield): mp: 122–123◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 3.37 (s, 3H), 5.06 (s, 2H), 5.63 (dd, J =
3.4 Hz, 1.5 Hz, 1H), 6.35 (t, J = 3.5 Hz, 1H), 6.92 (dd,
J = 3.3 Hz, 1.5 Hz, 1H), 7.21–7.37 (m, 3H), 7.47 (d,
J = 6.7 Hz, 2H); 13C-NMR (75 MHz, DMSO-d6) δ
ppm: 32.82, 46.94, 93.48, 111.09, 113.20, 128.34,
128.65 (2C), 128.82 (2C), 130.71, 135.12, 148.26; ESI-
MS: 292.4 [M+H]+, 314.4 [M+Na]+.
Compound 9 (Table 1, entry 1). Colorless crys-
Compound 14 (Table 1, entry 6). White solid
(67% yield): mp: 94–97◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 1.31 (t, J = 7.1 Hz, 3H), 3.90 (q,
J = 7.1 Hz, 2H), 5.06 (s, 2H), 5.66 (dd, J = 3.5 Hz,
1.5 Hz, 1H), 6.36 (t, J = 3.5 Hz, 1H), 6.92 (dd, J =
3.4 Hz, 1.6 Hz, 1H), 7.25–7.36 (m, 3H), 7.43–7.45 (d,
J = 6.8 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ ppm:
14.03, 47.35, 62.03, 93.46, 111.36, 113.11, 128.38
(2C), 128.68 (2C), 129.84, 134.90, 148.51, 166.71;
ESI-MS: 306.4 [M+H]+.
1
tal (82% yield): mp: 99–100◦C. H-NMR (400 MHz,
CDCl3) δ ppm: 5.01 (s, 2H), 5.11 (s, 2H), 5.52 (dd,
J = 3.4 Hz, 1.2 Hz, 1H), 6.27 (t, J = 3.4 Hz,
1H), 6.91 (dd, J = 3.2 Hz, 1.2 Hz, 1H), 7.16 (m,
2H), 7.25–7.37 (m, 5H), 7.47 (d, J = 6.6 Hz, 2H);
13C-NMR (100 MHz, CDCl3) δ ppm: 47.30, 49.08,
94.76, 111.20, 113.20, 128.22, 128.44, 128.72, 128.78,
129.09, 129.68, 133.42, 133.84, 135.02, 148.64; ESI-
MS: 402.5 [M+H]+.
Compound 10 (Table 1, entry 2). White solid
(70% yield): mp: 102–103◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 4.98 (s, 2H), 5.10 (s, 2H), 5.57 (dd, J =
3.6 Hz, 1.6 Hz, 1H), 6.26 (t, J = 3.5 Hz, 1H), 6.82 (dd,
J = 6.7 Hz, 2.0 Hz, 2H), 6.89 (dd, J = 3.4 Hz, 1.6 Hz,
1H), 7.17 (d, J = 8.7 Hz, 1H), 7.30–7.37 (m, 3H),
7.47 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ ppm:
47.29, 49.06, 94.76, 111.23, 113.25, 122.95, 125.28,
128.44, 128.73 (4C), 129.60, 129.90, 130.48, 131.15,
134.97, 137.21, 148.61; ESI-MS: 446.4 [M+H]+,
448.3 [M+H]+, 468.2 [M+Na]+, 470.3 [M+Na]+.
Compound 15 (Table 1, entry 7). White solid
(75% yield): mp: 86–88◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 2.3 (s, 3H), 5.00 (s, 2H), 5.11 (s, 2H),
5.55 (dd, J = 3.5 Hz, 1.5 Hz, 1H), 6.25 (t, J = 3.5 Hz,
1H), 6.89 (dd, J = 3.4 Hz, 1.5 Hz, 1 H), 7.09–7.14 (m,
4H), 7.30–7.36 (m, 3H), 7.47 (d, J = 2.6 Hz, 2H);
13C-NMR (100 MHz, CDCl3) δ ppm: 21.09, 47.16,
49.57, 94.81, 110.94, 113.24, 126.83, 128.34, 128.69,
128.77, 129.53, 129.94, 131.89, 135.174, 148.64; ESI-
MS: 382.5 [M+H]+, 404.5 [M+Na]+.
Compound 16 (Table 1, entry 8). Colorless oil
(78% yield). 1H-NMR (400 MHz, CDCl3) δ ppm: 4.61
(dd, J = 6.0 Hz, 1.4 Hz, 2H), 5.09 (s, 2H), 5.72 (dd,
J = 3.6 Hz, 1.6 Hz, 1H), 6.18–6.23 (m, 1H), 6.33 (t,
J = 3.4 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 6.93 (dd,
J = 3.4 Hz, 1.6 Hz, 1H), 7.25–7.34 (m, 8H), 7.34 (d,
J = 1.4 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ ppm:
47.12, 48.52, 94.28, 110.99, 113.30, 121.73, 126.60
(2C), 128.16, 128.40, 128.63 (2C), 128.72 (2C), 128.85
(2C), 129.88, 133.89, 135.13, 135.88, 148.14; ESI-MS:
394.5 [M+H]+, 411.4 [M+NH4]+, 416.5 [M+Na]+.
Compound 11 (Table 1, entry 3). White solid
(75% yield): mp: 89–90◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 5.04 (s, 2H), 5.12 (s, 2H), 5.52 (dd, J =
3.6 Hz, 1.6 Hz, 1H), 6.27 (t, J = 3.4 Hz, 1H), 6.92–7.02
(m, 4H), 7.26–7.37 (m, 4H), 7.47 (m, 2H); 13C-NMR
(100 MHz, CDCl3) δ ppm: 47.33, 49.21 (d, J = 1.7 Hz),
94.76, 111.21, 113.23, 113.88 (d, J = 22.3 Hz), 151.66
(d, J = 21.0 Hz), 122.34 (d, J = 3.0 Hz), 128.45, 128.73
(2C), 128.77 (2C), 129.70, 130.51 (d, J = 8.3 Hz),
135.01, 137.45, (d, J = 7.1 Hz), 148.65, 163.08 (d, J =
245.8 Hz); ESI-MS: 386.5 [M+H]+, 408.4 [M+Na]+.
Compound 12 (Table 1, entry 4). White solid
(82% yield): mp: 85–86◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 1.23 (t, J = 7.1 Hz, 3H), 4.21 (q,
J = 7.1 Hz, 2H), 4.51 (s, 2H), 5.08 (s, 2H), 5.54 (dd, J =
3.6 Hz, 1.6 Hz, 1H), 6.32 (t, J = 3.5 Hz, 1H,), 6.93 (dd,
J = 3.4 Hz, 1.6 Hz, 1H), 7.25–7.36 (m, 3H), 7.45–7.47
Compound 17 (Table 1, entry 9). White solid
(65% yield): mp: 80–82◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 4.45 (d, J = 5.4 Hz, 1H), 5.07 (s, 2H),
5.24–5.28 (m, 2H), 5.65 (dd, J = 3.4 Hz, 1.4 Hz, 1H),
5.79–5.89 (m, 1H), 6.33 (t, J = 3.5 Hz, 1H), 6.92 (dd,
J = 3.4 Hz, 1.5 Hz, 1H), 7.28–7.34 (m, 3H), 7.36 (d,
J = 2.0 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ ppm:
47.06, 48.71, 94.21, 110.95, 113.20, 118.36, 128.34,
128.67 (2C), 128.79 (2C), 129.87, 130.50, 135.13,
148.08; ESI-MS: 318.5 [M+H]+, 340.5 [M+Na]+.
3
(m, 2H); C-NMR (100 MHz, CDCl3): 47.15, 49.32,
55.26, 94.80, 110.94, 113.22, 114.26, 126.97, 128.35
(2C), 128.73 (2C), 129.92, 135.17, 148.63, 159.31;
ESI-MS: 364.4 [M+H] +, 386.5 [M+Na]+.
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of Derivatives of 1,1,3-Trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine 501
Compound 18 (Table 1, entry 10). White solid
110.88, 113.18, 126.83 (2C), 128.86 (2C), 129.37 (2C),
129.53 (2C), 129.93, 131.91, 132.18, 148.66; ESI-MS:
396.3 [M+H]+, 418.5 [M+Na]+.
(85% yield): mp: 95–98◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 2.34 (s, 3H), 5.00 (s, 2H), 5.07 (s, 2H),
5.51 (dd, J = 3.5 Hz, 1.5 Hz, 1H), 6.26 (t, J = 3.4 Hz,
1H), 6.90 (dd, J = 3.4 Hz, 1.4 Hz, 1H), 7.14–7.17 (m,
4H), 7.25–7.29 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H);
13C-NMR (100 MHz, CDCl3): 21.22, 47.16, 49.04,
94.68, 111.14, 113.14, 128.22 (2C), 128.87 (2C),
129.08 (2C), 129.41 (2C), 132.02, 133.45, 133.80,
138.31, 148.65; ESI-MS: 416.4 [M+H]+, 418.5
[M+H]+, 433.5 [M+NH4]+, 438.4 [M+Na]+, 440.5
[M+Na]+.
REFERENCES
[1] (a) Martinez, A.; Esteban, A. I.; Castro, A.; Gil,
C.; Conde, S.; Andrei, G.; Snoeck, R.; Balzarini, J.;
De Clercq, E. J Med Chem 1999, 42, 1145–1150;
(b) Martinez, A.; Esteban, A. I.; Clercq, E. D. Bioorg
Med Chem Lett 1997, 7, 1031–1132; (c) Martinez, A.;
Gil, C.; Perez, C.; Castro, A.; Prieto, C.; Otero, J.; An-
drei, G.; Snoeck, R.; Balzarini, J.; De Clercq, E. J Med
Chem 2000, 43, 3267–3273; (d) Martinez, A.; Gil, C.;
Abasolo, M. I.; Castro, A.; Bruno, A. M.; Perez, C.; Pri-
eto, C.; Otero, J. J Med Chem 2000, 43, 3218–3225;
(e) Martinez, A.; Gil, C.; Castro, A.; Perez, C.;
Witvrouw, M.; Pannecouque, C.; Balzarini, J.; De
Clercq, E. Antiviral Chem Chemother 2002, 12, 347–
351.
[2] (a) Witvrouw, M.; Arranz, M. E.; Pannecouque, C.;
Declercq, R.; Jonckheere, H.; Schmit, J. C.; Van-
damme, A. M.; Diaz, J. A.; Ingate, S. T.; Desmyter,
J.; Esnouf, R.; Van Meervelt, L.; Vega, S.; Balzarini,
J.; De Clercq, E. Antimicrob Agents Chemother 1998,
42, 618–623; (b) Arranz, M. E.; D´ıaz, J. A.; Ingate,
S. T.; Witvrouw, M.; Pannecouque, C.; Balzarini, J.;
De Clercq, E.; Vega, S. Bioorg Med Chem 1999, 7,
2811–2822.
Compound 19 (Table 1, entry 11). White solid
(78% yield): mp: 88–90◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 2.32 (s, 3H), 5.03 (s, 2H), 5.08 (s,
2H), 5.51 (dd, J = 3.5 Hz, 1.5 Hz, 1H), 6.26 (t,
J = 3.5 Hz, 1H), 6.90 (dd, J = 3.5 Hz, 1.5 Hz, 1H),
6.94–7.01 (m, 3H), 7.15 (d, J = 7.9 Hz, 2H), 7.25–
7.28 (m, 1H), 7.37 (d, J = 8.0 Hz, 2H); 13C-NMR
(100 MHz, CDCl3): 21.18, 47.24, 49.21 (d, J = 1.8 Hz),
94.67, 111.18, 113.16, 113.89 (d, J = 21.3 Hz), 114.91
(d, J = 21.1 Hz), 122.34 (d, J = 2.9 Hz), 128.85,
129.42 (2C), 129.77 (2C), 130.50 (d, J = 8.1 Hz),
132.06, 137.53 (d, J = 7.3 Hz), 138.31, 148.70, 163.11
(d, J = 245.5 Hz); ESI-MS: 400.3 [M+H]+, 417.5
[M+NH4]+, 422.4 [M+Na]+.
[3] Arranz, E.; Diaz, J. A.; Ingate, S. T.; Witvrouw, M.;
Pannecouque, C.; Balzarini, J.; De Clercq, E.; Vega,
S. J Med Chem 1998, 41, 4109–4117.
[4] Lin, Y. Q.; Liu, X. Y.; Yan, R. Z.; Li, J.; Pannecouque,
C.; Witvrouw, M.; De Clercq, E. Bioorg Med Chem
2008, 16, 157–163.
[5] Yan, R. Z.; Liu, X. Y.; Xu, W. F.; Pannecouque, C.;
Witvrouw, M.; De Clercq, E. Arch Pharm Res 2006,
29, 957–962.
[6] Liu, X. Y.; Yan, R. Z.; Wang, Y.; Zhan, P.; De Clercq,
E.; Pannecouque, C.; Witvrouw, M.; Molina, M. T.;
Vega, S. Arch Pharm (Weinheim) 2008, 341, 216–222.
[7] (a) Ilankumaran, P.; Kisanga, P.; Verkade, J. G. Het-
eroat Chem 2001, 12, 561–562; (b) Fathalla, W.; Ali,
I. A. Heteroat Chem 2007, 18, 637–643; (c) Ali, I. A.;
Al-Masoudi, I. A.; Saeed, B.; Al-Masoudi, N. A.; La
Colla, P., Heteroat Chem 2005, 16, 148–155.
[8] (a) Liang, H. Synlett 2008, 2554–2555; (b) Sawada,
D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Tetra-
hedron Lett 2006, 47, 7219–7223; (c) Sawada, D.;
Sasayama, S.; Takahashi, H.; Ikegami, S. Tetrahe-
dron 2008, 64, 8780–8788.
Compound 20 (Table 1, entry 12). White solid
(72% yield): mp: 98–100◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 2.33 (s, 3H), 3.76 (s, 3H), 4.98 (s,
2H), 5.07 (s, 2H), 5.56 (dd, J = 3.5 Hz, 1.5 Hz, 1H),
6.25 (t, J = 3.5 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H),
6.88 (dd, J = 3.4 Hz, 1.5 Hz, 1H), 7.14–7.18 (m, 4H),
7.37 (d, J = 8.0 Hz, 2H); 13C-NMR (100 MHz, CDCl3)
δ ppm: 21.19, 47.05, 49.32, 55.28, 94.73, 110.91,
113.51, 114.29 (2C), 127.05, 128.36 (2C), 128.85 (2C),
129.37 (2C), 129.98, 132.22, 138.18, 148.69, 159.34;
ESI-MS: 412.5 [M+H]+, 429.5 [M+NH4]+, 434.5
[M+Na]+.
Compound 21 (Table 1, entry 13). White solid
(80% yield): mp: 92–94◦C. 1H-NMR (400 MHz,
CDCl3) δ ppm: 2.31 (s, 3H), 2.34 (s, 3H), 5.01 (s, 2H),
5.08 (s, 2H), 5.54 (dd, J = 3.5 Hz, 1.5 Hz, 1H), 6.25
(t, J = 3.5 Hz, 1H), 6.88 (dd, J = 3.4 Hz, 1.5 Hz, 1H),
7.07–7.16 (m, 6H), 7.37 (d, J = 8.0 Hz, 2H); 13C-NMR
(100 MHz, CDCl3): 21.11, 21.21, 47.02, 49.52, 94.74,
[9] Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron
1974, 30, 2151–2157.
[10] Liu, X. Y., Yan, R. Z.; Chen, N. G.; Xu, W. F.; Molina,
M. T.; Vega, S. Molecules 2006, 11, 827.
[11] Leogane, O.; Lebel, H. Synthesis 2009, 1935–1940.
Heteroatom Chemistry DOI 10.1002/hc