Unexpected heteroannulation and chlorination of benzothiadiazine derivatives mediated by DDQ

Article abstract of DOI:10.1055/s-0033-1340249

In the course of studies directed toward the synthesis of new tubulin polymerization inhibitors, several benzothiadiazine derivatives were prepared. The oxidative dehydrogenation reaction with DDQ unexpectedly led to heteroannulation and chlorination of the benzothiadiazine tricycles. A rationale for their formation is proposed.

Full text of DOI:10.1055/s-0033-1340249

PAPER
▌235
paper
Unexpected Heteroannulation and Chlorination of Benzothiadiazine Derivatives
Mediated by DDQ
Annulation and Chlorination of Benzothiadiazines with DDQ
Valerie Verones, Nathalie Flouquet, Amaury Farce, Pascal Berthelot, Nicolas Lebegue*
Laboratoire de Chimie Thérapeutique, UFR Pharmacie Univ Lille Nord de France, 59000 Lille, France
Fax +33(3)20964913; E-mail: nicolas.lebegue@univ-lille2.fr
Received: 09.09.2013; Accepted after revision: 21.10.2013
O
O
O
O
Abstract: In the course of studies directed toward the synthesis of
new tubulin polymerization inhibitors, several benzothiadiazine de-
rivatives were prepared. The oxidative dehydrogenation reaction
with DDQ unexpectedly led to heteroannulation and chlorination of
the benzothiadiazine tricycles. A rationale for their formation is
proposed.
S
O
S
N
N
n
N
N
N
5a n = 0
5b n = 1
1
Key words: benzothiadiazine, oxidative dehydrogenation, hetero-
annulation, radical reaction, diastereoselectivity
OMe
MeO
For some years, our research team has been interested in
synthesizing compounds having potential antitumoral
activity, especially inhibiting tubulin polymerization
(thiazepine, thiadiazepine, oxathiazepine, etc.).1 The ben-
zopyridooxathiazepine derivative 1 displayed potent in
vitro but moderately in vivo antitumor activities (Figure
1).2 Chemical and metabolic stability studies showed that
1 suffered from a lack of stability of the oxathiazepine
ring, which could have some consequences on the storage
conditions3 and the pharmacokinetic profile.4 Continuing
our search strategy for novel potent tubulin-targeting
compounds, we extended our studies by bioisosteric re-
placement of the oxathiazepine core with benzothiadia-
zine derivatives, leading to compounds 5a,b with
improved chemical stability, which were important scaf-
folds in medicinal chemistry5 and were in agreement with
the previously established structure–activity relation-
ships.
Figure 1 Benzopyridooxathiazepine derivative 1 and the targeted
compounds 5a,b
We planned to synthesize the target compounds 5a,b
starting with condensation of benzothiadiazine deriva-
tives 2a,b and methanesulfonate 3a followed by a key step
of oxidative dehydrogenation to produce the correspond-
ing unsaturated derivatives 5a,b (Scheme 1).
The production of heteroaromatics by oxidative dehydro-
genation is of fundamental importance in organic synthe-
sis. Many reagents can be employed to perform
dehydrogenation reactions, for example: sulfur, selenium
dioxide, nickel dioxide, manganese dioxide, quinones, tri-
phenylcarbenium tetrafluoroborate, and Pd/C.6 Among
these reagents, quinones of high oxidation potential are
powerful oxidants, which performed a large number of
useful reactions under relatively mild conditions. Within
this class, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
O
O
O
O
S
N
S
N
N
N
O
O
( )n
( )n
S
N
N
N
N
( )n
4a n = 0
4b n = 1
5a n = 0
5b n = 1
N
H
2a n = 0
2b n = 1
+
OMe
OMe
MeO
OSO2Me
3a
Scheme 1 Synthetic strategy leading to unsaturated benzothiadiazines by way of dehydrogenation reaction
SYNTHESIS 2014, 46, 0235–0241
Advanced online publication: 14.11.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340249; Art ID: SS-2013-T0617-OP
© Georg Thieme Verlag Stuttgart · New York

236
V. Verones et al.
PAPER
O
O
O
O
O
O
S
N
S
N
S
N
N
N
N
Cl
N
( )n
( )n
( )n
N
N
DDQ
5a n = 0
5b n = 1
4a n = 0
4b n = 1
toluene
6a n = 0
6b n = 1
MeO
OMe
OMe
not observed
Scheme 2 DDQ dehydrogenation of 4a,b
1
(DDQ) represents one of the more versatile reagents since scribed in detail in the Supporting Information. The H
it combines high oxidant ability with relative stability.7 NMR spectra of the isolated compounds contained one set
DDQ was a particularly effective aromatization reagent of signals, indicating the selective formation of one dia-
and was frequently the reagent of choice to effect facile stereomer, which was a racemic mixture of enantiomers.
dehydrogenation of both simple and complex hydroaro-
No traces of the other diastereomer were detected by
matic heterocyclic compounds. Following the synthetic
NMR spectrometry. The enantiomeric composition of the
strategic scheme previously described, benzothiadiazines
racemate 6b was demonstrated by chiral HPLC analysis.9
Thus, this reaction proceeded with high diastereoselection
to produce exclusively the syn- or anti-products. To as-
sign the complete stereochemistry of the cyclocondensed
2a,b8 were reacted with methanesulfonate 3a in the pres-
ence of sodium hydride in anhydrous DMF under nitrogen
atmosphere. The N-alkylated compounds 4a,b were then
refluxed in toluene with 2 equivalents of DDQ. This did
products by X-ray diffraction studies, the racemic sub-
not afford the desired unsaturated derivatives but other
strate 6b was resolved into its enantiomeric components
single products, which proved to be the cyclocondensed
by preparative chiral HPLC. Unfortunately, none of the
imidazobenzothiadiazines 6a,b bearing a chloro substitu-
separated stereoisomers formed crystals suitable for X-
ent and were isolated in only 25% yield (Scheme 2). The
structural assignments of 6a,b were based on extensive
NMR and high-resolution mass spectral analysis as de-
ray crystallography. Lowest energy conformational
search employing the Tripos force field10 was performed
for each stereoisomer of 6b with the Sybyl 6.9.1 molecu-
O–
O
O
O
O
O
S
N
NC
NC
Cl
S
N
NC
NC
Cl
Cl
N
N
+
+
( )n
( )n
N
Cl
N
I
H
O
O
4a,b
II
+
OMe
OMe
_
O
NC
NC
Cl
Cl
O
O
O
N
OH
O
O
III
S
NC
Cl
S
N
N
Cl
+
+
( )n
( )n
N
N
NC
H
N
O
O–
V
6a,b
VI
NC
NC
Cl
Cl
MeO
H
O
O
+
Me
IV
Scheme 3 Possible mechanism accounting for the formation of cyclocondensed benzothiadiazines 6a,b
Synthesis 2014, 46, 235–241
© Georg Thieme Verlag Stuttgart · New York

PAPER
Annulation and Chlorination of Benzothiadiazines with DDQ
237
lar modeling package.11 Only the stereoisomers derived uct subsequently as described during DDQ oxidation of
from the anti-cyclization seem to be formed, since the mo- dihydropyrimidine nucleoside derivatives.16 In the second
lecular mechanics calculations showed that the trans-con- hypothesis, a chloride ion is generated by the decomposi-
formers are 1.15 kcal/mol more stable than their cis- tion of DDQ in solvent17 and attacks the carbon of the gua-
counterparts,12 possibly because of the steric hindrance nidine group of V to provide the final chlorinated
between the chlorine atom and the p-anisole group.
compound.
A tentative mechanism for the reaction is proposed in The formation of a tetracycle of this type has not previous-
Scheme 3. Initial formation of a charge-transfer complex ly been reported, so several substrates were prepared to
from the electron-donating aromatic ring of 4-methoxy- explore the scope of the process, the capacity to effect di-
phenyl to electron-accepting DDQ generates a radical cat- astereoselective cyclization reactions, and the potential
ion I and a DDQ radical anion II according to the first step for expanding the scope of product ring sizes in the reac-
of deprotection of 4-methoxybenzyl (PMB) ethers with tion. The results of this study are shown in Table 1. Intro-
DDQ.13 The presence of electron-donating groups stabi- duction of 3,4-dimethoxy or 3,4,5-trimethoxyphenylethyl
lized the radical cation by increasing the bond dissociation side chain (Table 1, entries 3–5) led to the corresponding
energy of the scissile carbon–hydrogen bond.14 Thus, the cyclocondensed tetracycles 6c–e under DDQ oxidative
radical oxygen of the DDQ radical anion abstracts a ben- dehydrogenation while phenylethylbenzothiadiazine 4f
zyl H-atom from the radical cation and generates a stable (entry 6), which lacks methoxy substitution on the side
cyclohexadienylidene methyloxidanium cation V15 and chain, was inert under the reaction conditions, thereby
the corresponding phenoxide III. Two hypotheses can be demonstrating the importance of electron-rich methoxy-
envisioned to explain the basis of the source of the chlo- phenyl groups to stabilize the radical cation in this reac-
rine. The first, as described in Scheme 3, can result from tion. Higher cyclocondensed homologues cannot be
tautomerism of the phenoxide III, followed by extrusion formed through this method since heating 4-methoxy-
of the chloride ion from an sp3 hybridized carbon, which phenylpropyl derivative 4g (entry 7) with DDQ did not
can act as a nucleophile entity to drive the anti-selective lead to the desired tetracycle but to recovery of the starting
cyclization to completion of the reaction. A black polar in- material.
stable dechlorinated product VI is formed as a side prod-
Table 1 N-Alkykation and DDQ Reactiona
Entry
Substrate
Yield (%)b
Product
Yield (%)b
O
O
S
N
N
Cl
O
O
S
N
OMe
N
1
69
25
N
N
4a
MeO
6a
O
O
S
N
N
O
O
Cl
N
S
N
N
OMe
2
N
63
25
4b
MeO
6b
O
O
S
N
N
Cl
O
O
S
N
N
OMe
OMe
N
3
62
21
N
4c
OMe
MeO
6c
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 235–241

238
V. Verones et al.
PAPER
Table 1 N-Alkykation and DDQ Reactiona (continued)
Entry
Substrate
Yield (%)b
Product
Yield (%)b
O
O
S
N
N
O
O
Cl
N
S
N
OMe
OMe
4
66
22
N
N
4d
MeO
OMe
O
6d
O
S
N
O
O
Cl
N
S
N
N
OMe
N
OMe
OMe
N
5
72
23
MeO
MeO
4e
OMe
6e
O
O
S
N
N
N
6
7
38
53
no reactionc
–
–
4f
O
O
S
N
N
N
no reactionc
OMe
4g
a General procedure for DDQ reaction: substrate (1 equiv) and DDQ (2 equiv) were added to toluene, and heated under reflux for 12 h. See the
experimental section for details.
b Isolated yields of purified materials.
c Recovery of starting material.
Standard abbreviations are used to denote the signal multiplicities.
HPLC-MS analyses were accomplished using a HPLC instrument
combined with a Surveyor MSQ (Thermo Electron) equipped with
an APCI source (ODS-30 column, mobile phase of H2O–MeCN–
HCO2H, gradient mode). Elemental analyses were performed by
C.N.R.S-Vernaison, and were in agreement with the calculated val-
ues within ± 0.4%. Analytical chiral HPLC method: Waters HPLC
system was equipped with a HPLC 600 pump and a 2996 photodi-
ode array detector. The HPLC analysis were performed on a Daicel
Chiralpak AD Column (250 × 4.6 mm) eluting with PE–i-PrOH at
1 mL/min. Preparative chiral HPLC method: VWR HPLC system
was equipped with a HPLC P110 pump and a P311 UV detector
(wavelength 253 nm). HPLC resolution was performed on a Daicel
Chiralpak AD Column (200 × 50 mm) eluting with PE–i-PrOH at
90.0 mL/min, 100 mg per injection.
In conclusion, we have reported the unexpected annula-
tion and chlorination of benzothiadiazine derivatives dur-
ing DDQ oxidation. We have demonstrated that the DDQ-
induced oxidative N–C bond coupling reaction proceeded
with high diastereoselection to produce the supposed
trans-stereoisomers as determined by molecular mechan-
ics calculations. Further work based on chlorine replace-
ment by various nucleophiles is ongoing and could be
employed as intermediates in the synthesis of expected
bioactive compounds.
All reagents and solvents were purchased from commercial sources
and used without further purification. Petroleum ether (PE) used re-
fers to the fraction boiling in the 40–60 °C range. Melting points
were determined on a Büchi B-540 apparatus and are uncorrected.
NMR spectra were acquired using NMR spectrometer operating at
300 MHz (1H) or 75 MHz (13C). Chemical shifts are given in ppm.
N-Alkylated Benzothiadiazines 4; General Procedure
A solution of respective benzothiadiazine 2a,b (2 mmol) in anhy-
drous DMF (30 mL) was added dropwise to a suspension of NaH
(96 mg, 4 mmol) in anhydrous DMF (5 mL) and stirred for 3 h at
Synthesis 2014, 46, 235–241
© Georg Thieme Verlag Stuttgart · New York

PAPER
Annulation and Chlorination of Benzothiadiazines with DDQ
239
60 °C under N2 atmosphere. A solution of the previously synthe-
sized appropriate arylalkyl methanesulfonate 3 (6 mmol) in anhy-
drous DMF (10 mL) was then added dropwise to the above solution
and stirred for 24 h at 60 °C under N2 atmosphere. The resulting so-
lution was concentrated under reduced pressure and the residue was
diluted with EtOAc (30 mL). The EtOAc layer was washed with
H2O (20 mL) and dried (Na2SO4). The solvent was evaporated in
vacuo and the residual material was precipitated by addition of
Et2O, filtered, and recrystallized from EtOH.
6.84 (m, 3 H), 7.12 (t, J = 7.5 Hz, 1 H), 7.28 (m, 1 H), 7.52 (td,
J = 1.5, 8.5 Hz, 1 H), 7.73 (dd, J = 1.5, 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.7, 33.1, 39.1, 47.5, 52.4, 55.9,
111.2, 112.1, 120.8, 121.2, 121.6, 123.8, 125.5, 131.7, 133.5, 147.0,
147.6, 149.0.
LC/MS (APCI+): m/z = 402.3 [M + H]+.
Anal. Calcd for C20H23N3O4S: C, 59.83; H, 5.77; N, 10.47. Found:
C, 59.94; H, 5.63; N, 10.60.
1-[2-(4-Methoxyphenyl)ethyl]-2,3-dihydroimidazo[1,2-
b][1,2,4]benzothiadiazine 5,5-Dioxide (4a)
1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-1,2,3,4-tetrahydropyrim-
idino[1,2-b][1,2,4]benzothiadiazine 6,6-Dioxide (4e)
Yield: 0.62 g (72%); white solid; mp 144–146 °C.
IR (KBr): 2943, 1517, 1502 cm–1.
Yield: 0.49 g (69%); white solid; mp 76–78 °C.
IR (KBr): 3060, 1589, 1515 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.96 (t, J = 7.3 Hz, 2 H), 3.42 (t,
J = 7.2 Hz, 2 H), 3.69 (m, J = 7.3 Hz, 2 H), 3.88 (s, 3 H), 4.00 (m,
2 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.18 (m, 3 H), 7.37 (dd, J = 2.0, 7.8
Hz, 1 H), 7.55 (td, J = 2.0, 7.8 Hz, 1 H), 7.84 (dd, J = 0.8, 7.5 Hz, 1
H).
13C NMR (75 MHz, CDCl3): δ = 32.6, 38.9, 44.5, 46.6, 55.3, 114.1,
122.1, 122.5, 122.9, 125.8, 129.7, 130.5, 134.1, 145.7, 152.0, 158.4.
1H NMR (300 MHz, CDCl3): δ = 2.01 (m, 2 H), 3.01 (t, J = 6.95 Hz,
2 H), 3.16 (t, J = 6.15 Hz, 2 H), 3.82 (m, 5 H), 3.85 (m, 8 H), 6.47
(s, 2 H), 7.11 (t, J = 7.95 Hz, 1 H), 7.27 (m, 1 H), 7.52 (td, J = 1.35,
8.5 Hz, 1 H), 7.73 (dd, J = 1.3, 7.85 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.7, 33.9, 39.1, 47.5, 52.2, 56.1,
60.9, 105.7, 121.2, 121.6, 123.9, 125.5, 133.5, 135.0, 136.5, 144.6,
146.9, 153.3.
LC/MS (APCI+): m/z = 358.1 [M + H]+.
LC/MS (APCI+): m/z = 432.5 [M + H]+.
Anal. Calcd for C18H19N3O3S: C, 60.49; H, 5.36; N, 11.76. Found:
C, 60.54; H, 5.28; N, 11.82.
Anal. Calcd for C21H25N3O5S: C, 58.45; H, 5.84; N, 9.74. Found: C,
58.54; H, 5.76; N, 9.80.
1-[2-(4-Methoxyphenyl)ethyl]-1,2,3,4-tetrahydropyrimidi-
no[1,2-b][1,2,4]benzothiadiazine 6,6-Dioxide (4b)
Yield: 0.48 g (65%); beige solid; mp 105–107 °C.
IR (KBr): 2937, 1519, 1490 cm–1.
1-(2-Phenylethyl)-1,2,3,4-tetrahydropyrimidino[1,2-
b][1,2,4]benzothiadiazine 6,6-Dioxide (4f)
Yield: 0.26 g (38%); colorless oil.
IR (film): 3032, 1571, 1512 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.04 (t, J = 7.2 Hz, 2 H), 3.00 (t,
J = 7.1 Hz, 2 H), 3.19 (t, J = 7.3 Hz, 2 H), 3.80 (s, 3 H), 3.86 (m, 4
H), 6.86 (d, J = 8.6 Hz, 2 H), 7.11 (t, J = 8.0 Hz, 1 H), 7.17 (d,
J = 8.6 Hz, 2 H), 7.29 (d, J = 8.5 Hz, 1 H), 7.52 (td, J = 1.5, 8.5 Hz,
1 H), 7.74 (dd, J = 1.5, 8.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.7, 32.5, 39.1, 47.3, 52.3, 55.3,
113.9, 121.1, 121.5, 123.8, 125.7, 129.9, 131.2, 133.5, 144.8, 146.9,
158.0.
1H NMR (300 MHz, CDCl3): δ = 2.01 (m, 2 H), 3.06 (t, J = 7.6 Hz,
2 H), 3.19 (t, J = 5.8 Hz, 2 H), 3.84 (m, 4 H), 7.11 (td, J = 1.1, 8.3
Hz, 1 H), 7.21–7.35 (m, 6 H), 7.52 (td, J = 1.6, 7.3 Hz, 1 H), 7.74
(dd, J = 1.65, 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.6, 33.4, 39.0, 47.2, 52.1, 121.1,
121.5, 123.7, 125.6, 126.4, 128.5, 128.9, 133.4, 139.1, 144.6, 146.9.
LC/MS (APCI+): m/z = 342.3 [M + H]+.
Anal. Calcd for C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31. Found:
C, 63.41; H, 5.55; N, 12.44.
LC/MS (APCI+): m/z = 372.1 [M + H]+.
Anal. Calcd for C19H21N3O3S: C, 61.44; H, 5.70; N, 11.31. Found:
C, 61.50; H, 5.65; N, 11.38.
1-[3-(4-Methoxyphenyl)propyl]-1,2,3,4-tetrahydropyrimidi-
no[1,2-b][1,2,4]benzothiadiazine 6,6-Dioxide (4g)
Yield: 0.30 g (39%); colorless oil.
IR (film): 2954, 1568, 1520 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.04 (m, 2 H), 2.14 (m, 2 H), 2.68
(t, J = 7.4 Hz, 2 H), 3.41 (t, J = 6.1 Hz, 2 H), 3.72 (m, 2 H), 3.82 (s,
3 H), 3.88 (t, J = 5.7 Hz, 2 H), 6.84 (d, J = 8.3 Hz, 2 H), 7.14 (m, 3
H), 7.52 (t, J = 7.1 Hz, 1 H), 7.73 (d, J = 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.3, 28.5, 32.1, 46.9, 51.9, 54.8,
113.5, 120.7, 121.1, 123.3, 125.2, 129.5, 130.7, 133.1, 145.1, 151.4,
157.8.
1-[2-(3,4-Dimethoxyphenyl)ethyl]-2,3-dihydroimidazo[1,2-
b][1,2,4]benzothiadiazine 5,5-Dioxide (4c)
Yield: 0.48 g (62%); beige solid; mp 95–97 °C.
IR (KBr) 3024, 1521, 1497 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.94 (t, J = 6.9 Hz, 2 H), 3.40 (t,
J = 7.9 Hz, 2 H), 3.74 (t, J = 6.9 Hz, 2 H), 3.87 (s, 3 H), 3.88 (s, 3
H), 3.99 (t, J = 7.4 Hz, 2 H), 6.80 (m, 3 H), 7.18 (t, J = 7.1 Hz, 1 H),
7.33 (d, J = 8.4 Hz, 1 H), 7.54 (td, J = 1.5, 8.6 Hz, 1 H), 7.84 (dd,
J = 1.35, 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 33.1, 38.9, 44.6, 46.4, 55.9, 111.3,
111.8, 120.6, 122.1, 122.6, 122.8, 125.5, 130.9, 134.1, 147.7, 149.0,
152.0.
LC/MS (APCI+): m/z = 386.2 [M + H]+.
Anal. Calcd for C20H23N3O3S: C, 62.32; H, 6.01; N, 10.90. Found:
C, 62.45; H, 5.88; N, 10.97.
LC/MS (APCI+): m/z = 388.2 [M + H]+.
Anal. Calcd for C19H21N3O4S: C, 58.90; H, 5.46; N, 10.85. Found:
C, 59.08; H, 5.36; N, 10.97.
Annulated Benzothiadiazines 6; General Procedure
A solution of the respective benzothiadiazine 4a–g (0.5 mmol) and
DDQ (227 mg, 1 mmol) was heated at reflux for 12 h in toluene (25
mL). The resulting black mixture was filtered, evaporated under re-
duced pressure, and the residual material was purified by flash chro-
matography on silica gel eluting with 9:1 CH2Cl2–EtOAc.
1-[2-(3,4-Dimethoxyphenyl)ethyl]-1,2,3,4-tetrahydropyrimidi-
no[1,2-b][1,2,4]benzothiadiazine 6,6-Dioxide (4d)
Yield: 0.48 g (60%); white solid; mp 109–111 °C.
IR (KBr) 2975, 1525, 1512 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.01 (m, 2 H), 3.02 (t, J = 7.2 Hz,
2 H), 3.15 (t, J = 6.2 Hz, 2 H), 3.83 (m, 4 H), 3.87 (m, 6 H), 6.77–
12a-Chloro-1-(4-methoxyphenyl)-1,2,4,5-tetrahydrodiimid-
azo[1,2-a][2,1-b][1,2,4]benzothiadiazine 7,7-Dioxide (6a)
Yield: 0.05 g (25%); beige solid; mp 165–167 °C; analytical chiral
HPLC: 70:30 PE–i-PrOH, tR = 16.00 and 18.92 min.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 235–241

240
V. Verones et al.
PAPER
IR (KBr): 3076, 1613, 1511 cm–1.
Anal. Calcd for C20H22ClN3O4S: C, 55.10; H, 5.09; N, 9.64. Found:
C, 55.22; H, 5.01; N, 9.74.
1H NMR (300 MHz, CDCl3): δ = 3.66 (dd, J = 5.8, 9.2 Hz, 1 H),
3.73–3.84 (m, 5 H), 3.93 (m, 1 H), 4.14 (dd, J = 7.1, 14.3 Hz, 1 H),
4.39 (t, J = 9.6 Hz, 1 H), 5.42 (dd, J = 6.0, 9.7 Hz, 1 H), 6.71 (d,
J = 8.3 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.27 (m, 3 H), 7.36 (t,
J = 7.7 Hz, 1 H), 7.97 (dd, J = 1.3, 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 42.2, 46.9, 55.4, 55.5, 58.8, 114.1,
115.1, 123.0, 124.3, 124.8, 126.9, 129.4, 132.4, 134.7, 153.4, 160.2.
13a-Chloro-1-(3,4,5-trimethoxyphenyl)-1,2,dihydroimid-
azo[1,2-a]-4,5,6-trihydropyrimido[2,1-b][1,2,4]benzothiadia-
zine 8,8-Dioxide (6e)
Yield: 0.053 g (23%); beige solid; mp 124–126 °C; analytical chiral
HPLC: 70:30 PE–i-PrOH, tR = 13.59 and 17.86 min.
IR (KBr): 2984, 1609, 1515 cm–1.
LC/MS (APCI+): m/z = 392.1 [M + H]+, 394.1 [M + 2 + H]+.
1H NMR (300 MHz, CDCl3): δ = 2.16 (m, 2 H), 3.41 (dd, J = 5.7,
9.6 Hz, 1 H), 3.43–3.58 (m, 4 H), 3.88 (s, 3 H), 3.94 (s, 6 H), 4.19
(t, J = 9.9 Hz, 1 H), 5.36 (dd, 6.0, 9.9 Hz, 1 H), 6.52 (s, 2 H), 6.69
(d, J = 8.1 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1
H), 7.92 (dd, J = 1.5, 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 31.9, 41.9, 42.5, 54.2, 56.3, 58.9,
60.8, 102.0, 114.0, 123.0, 124.4, 124.6, 132.5, 133.2, 134.7, 138.3,
153.8, 154.4.
Anal. Calcd for C18H18ClN3O3S: C, 55.17; H, 4.63; N, 10.72.
Found: C, 55.31; H, 4.54; N, 10.82.
13a-Chloro-1-(4-methoxyphenyl)-1,2,dihydroimidazo[1,2-a]-
4,5,6-trihydropyrimido[2,1-b][1,2,4]benzothiadiazine 8,8-Diox-
ide (6b)
Yield: 0.05 g (25%); beige solid; mp 154–156 °C; analytical chiral
HPLC: 60:40 PE–i-PrOH, tR = 10.65 and 14.63 min; preparative
chiral HPLC: 60:40 PE–i-PrOH, tR = 19.5 and 32.4 min.
LC/MS (APCI+): m/z = 466.3 [M + H]+, 468.3 [M + 2 + H]+.
IR (KBr): 2949, 1605, 1515 cm–1.
Anal. Calcd for C21H24ClN3O5S: C, 54.13; H, 5.19; N, 9.02. Found:
C, 54.25; H, 5.11; N, 9.14.
1H NMR (300 MHz, CDCl3): δ = 2.16 (m, 2 H), 3.50 (dd, J = 5.9,
9.3 Hz, 1 H), 3.59–3.67 (m, 4 H), 3.80 (s, 3 H), 4.20 (t, J = 9.6 Hz,
1 H), 5.38 (dd, J = 5.8, 9.7 Hz, 1 H), 6.67 (d, J = 8.4 Hz, 1 H), 6.92
(d, J = 8.8 Hz, 2 H), 7.20–7.27 (m, 3 H), 7.34 (td, J = 1.6, 7.8 Hz, 1
H), 7.96 (dd, J = 1.6, 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 29.9, 41.9, 42.6, 54.5, 55.4, 58.5,
114.0, 115.2, 122.7, 123.1, 124.2, 124.8, 129.4, 132.3, 160.1, 160.3,
161.5.
Acknowledgment
We thank Laboratoire d’Application de Résonnance Magnétique
Nucléaire de l’Université de Lille 2 for its help in the interpretation
of the NMR spectra.
LC/MS (APCI+): m/z = 406.0 [M + H]+, 408.0 [M + 2 + H]+.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Anal. Calcd for C19H20ClN3O3S: C, 56.22; H, 4.97; N, 10.35.
Found: C, 56.29; H, 4.88; N, 10.27.
12a-Chloro-1-(3,4-dimethoxyphenyl)-1,2,4,5-tetrahydrodiimid- References
azo[1,2-a][2,1-b][1,2,4]benzothiadiazine 7,7-Dioxide (6c)
(1) (a) Gallet, S.; Lebegue, N.; Flouquet, N.; Berthelot, P.;
Pierre, A.; Renard, P.; Pfeiffer, B. International Patent PCT
FR 04/00234, 2004. (b) Gallet, S.; Lebegue, N.; Flouquet,
N.; Berthelot, P.; Pierre, A.; Renard, P.; Pfeiffer, B.
International Patent PCT FR 04/00235, 2004. (c) Lebegue,
N.; Gallet, S.; Flouquet, N.; Carato, P.; Pfeiffer, B.; Renard,
P.; Leonce, S.; Pierre, A.; Chavatte, P.; Berthelot, P. J. Med.
Chem. 2005, 48, 7363.
(2) Gallet, S.; Flouquet, N.; Carato, P.; Pfeiffer, B.; Renard, P.;
Leonce, S.; Pierre, A.; Berthelot, P.; Lebegue, N. Bioorg.
Med. Chem. 2009, 17, 1132.
(3) Lecoeur, M.; Verones, V.; Vaccher, C.; Bonte, J. P.;
Lebegue, N.; Goossens, J. F. Eur. J. Pharm. Sci. 2012, 45,
559.
(4) Bourdon, F.; Lecoeur, M.; Verones, V.; Vaccher, C.;
Lebegue, N.; Dine, T.; Kambia, N.; Goossens, J. F.
J. Pharm. Biomed. Anal. 2013, 80, 69.
(5) (a) Chern, J. W.; Tao, P. L.; Wang, K. C.; Gutcait, A.; Liu,
S. W.; Yen, M. H.; Chien, S. L.; Rong, J. K. J. Med. Chem.
1998, 41, 3128. (b) Boverie, S.; Antoine, M. H.; de Tullio,
P.; Somers, F.; Becker, B.; Sebille, S.; Lebrun, P.; Pirotte, B.
J. Pharm. Pharmacol. 2001, 53, 973.
(6) (a) Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 78, 317.
(b) Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1992.
(7) (a) Jackman, L. M. Adv. Org. Chem. 1960, 2, 329.
(b) Ahluwalia, V. K.; Ghazanfari, F. A.; Arora, K. K.
Synthesis 1981, 526. (c) Ahluwalia, V. K.; Jolly, R. S.
Synthesis 1982, 74. (d) Fu, P. P.; Harvey, R. G. Tetrahedron
Lett. 1977, 2059. (e) Abad, A.; Agulló, C.; Arnó, M.;
Domingo, L. R.; Zaragozá, R. J. J. Org. Chem. 1988, 53,
3761.
Yield: 0.04 g (21%); beige solid; mp 133–135 °C; analytical chiral
HPLC: 70:30 PE–i-PrOH, tR = 15.91 and 19.28 min.
IR (KBr): 3052, 1607, 1501 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.65 (dd, J = 5.5, 8.8 Hz, 1 H),
3.73–3.99 (m, 9 H), 4.19 (dd, J = 6.9, 13.7 Hz, 1 H), 4.44 (t, J = 8.9
Hz, 1 H), 5.39 (dd, J = 6.1, 9.5 Hz, 1 H), 6.71 (d, J = 8.1 Hz, 1 H),
6.78 (s, 1 H), 6.87 (s, 2 H), 7.25 (m, 1 H), 7.35 (m, 1 H), 7.97 (dd,
J = 1.4, 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 42.2, 46.9, 54.4, 55.9, 56.0, 58.7,
107.8, 112.8, 114.0, 117.8, 123.0, 124.2, 124.6, 129.8, 132.3, 134.7,
149.6, 150.1, 153.7.
LC/MS (APCI+): m/z = 422.4 [M + H]+, 424.4 [M + 2 + H]+.
Anal. Calcd for C19H20ClN3O4S: C, 54.09; H, 4.78; N, 9.96. Found:
C, 54.18; H, 4.69; N, 10.05.
13a-Chloro-1-(3,4-dimethoxyphenyl)-1,2,dihydroimidazo[1,2-
a]-4,5,6-trihydropyrimido[2,1-b][1,2,4]benzothiadiazine 8,8-Di-
oxide (6d)
Yield: 0.048 g (22%); beige solid; mp 108–110 °C; analytical chiral
HPLC: 60:40 PE–i-PrOH, tR = 10.50 and 14.16 min.
IR (KBr): 3022, 1612, 1507 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.15 (m, 2 H), 3.51 (dd, J = 5.9,
9.7 Hz, 1 H), 3.58–3.68 (m, 4 H), 3.84 (s, 3 H), 3.87 (s, 3 H), 4.21
(t, J = 9.6 Hz, 1 H), 5.38 (dd, 5.8, 9.8 Hz, 1 H), 6.71 (d, J = 8.3 Hz,
1 H), 6.77 (s, 1 H), 6.86 (m, 2 H), 7.22 (t, J = 7.7 Hz, 1 H), 7.34 (t,
J = 7.7 Hz, 1 H), 7.94 (dd, J = 1.6, 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 29.9, 41.9, 42.6, 54.4, 56.0, 56.1,
58.7, 107.8, 111.8, 114.0, 117.9, 123.1, 124.2, 124.7, 129.9, 132.3,
134.8, 149.6, 150.1, 153.7.
LC/MS (APCI+): m/z = 436.0 [M + H]+, 438.0 [M + 2 + H]+.
Synthesis 2014, 46, 235–241
© Georg Thieme Verlag Stuttgart · New York

PAPER
Annulation and Chlorination of Benzothiadiazines with DDQ
241
(8) (a) Chern, J. W.; Rong, J. G. Tetrahedron Lett. 1991, 32,
(13) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885. (b) Chandrasekhar, S.; Sumithra, G.;
Yadav, J. S. Tetrahedron Lett. 1996, 37, 1645.
(c) Weissman, S. A.; Zewge, D. Tetrahedron 2005, 61,
7833.
2935. (b) Chern, J. W.; Liaw, Y. C.; Chen, C. S.; Rong, J. G.;
Huang, C. L.; Chan, C. H.; Wang, A. H. J. Heterocycles
1993, 36, 1091.
(9) See experimental for details.
(10) Clark, M.; Cramer, R. D. III.; van Opdenbosch, N.
J. Comput. Chem. 1989, 10, 982.
(11) SYBYL 6.9.1, Tripos Inc., 1699 South Hanley Road, St.
Louis, MO 63144-2913, USA.
(12) Respectively, 13.47 and 13.75 kcal/mol for the trans-
conformers and 14.62 and 14.91 kcal/mol for the cis-
conformers. See Supporting Information for details.
(14) Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 10830.
(15) Navale, T. S.; Thakur, K.; Rathore, R. Org. Lett. 2011, 13,
1634.
(16) Pragnacharyulu, P. V. P.; Abushanab, E. Tetrahedron Lett.
1997, 38, 3683.
(17) Ito, S.; Phong, L. T.; Komatsu, T.; Igarashi, N.; Otsubo, S.;
Sakai, Y.; Ohno, A.; Aramaki, S.; Tanaka, Y.; Uno, H.; Oba,
T.; Hiratani, K. Eur. J. Org. Chem. 2009, 5373.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 235–241