A noncatalytic approach to hetaryl-annulated 1,2,4-thiadiazine-1,1-dioxides

Article abstract of DOI:10.1002/jhet.1029

A set of synthetic procedures was developed to yield functionalized pyrido-, pyrimido-, and thiazo-annulated thiadiazine-1,1-dioxides on a preparative scale. In all cases the thiadiazine-1,1-dioxide ring closure was carried out through a reaction of hetaryl-sulfonyl chlorides with amidines under mild noncatalytic conditions. In the case of 2-chloropyridine-3-sulfonyl chloride derivatives and 2,4-dichlorothiazole-5-sulfonyl chloride open-chain sulfonylated amidine intermediates were isolated and then subjected to the cyclization step. The reaction with 2,4-dichloropyrimidine-5-sulfonyl chloride gave rise to the corresponding thiadiazine-1,1-dioxides in one-pot. Similarly, a reaction of 2-chloropyridine-3-sulfonamide with lactime ethers proceeded in one-pot readily giving the corresponding thiadiazine-1,1-dioxides. Remaining chlorine atoms on the prepared hetaryl-annulated benzothiadiazine-1,1-dioxides readily undergo aromatic nucleophilic displacement reactions serving thus as additional variation points for the design of biologically potent compounds.

Full text of DOI:10.1002/jhet.1029

Month 2013
A Noncatalytic Approach to Hetaryl-Annulated
1,2,4-Thiadiazine-1,1-dioxides
Artem Cherepakha,a Vladimir O. Kovtunenko,a Andrey Tolmachev,a,b
and Oleg Lukina,b
*
aChemBioCenter, National Taras Shevchenko University, Kiev 01033, Ukraine
bEnamine Ltd., Kiev 01103, Ukraine
*
E-mail: oleg.lukin@univ.kiev.ua
Received April 8, 2011
DOI 10.1002/jhet.1029
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A set of synthetic procedures was developed to yield functionalized pyrido-, pyrimido-, and thiazo-
annulated thiadiazine-1,1-dioxides on a preparative scale. In all cases the thiadiazine-1,1-dioxide ring closure
was carried out through a reaction of hetaryl-sulfonyl chlorides with amidines under mild noncatalytic
conditions. In the case of 2-chloropyridine-3-sulfonyl chloride derivatives and 2,4-dichlorothiazole-5-
sulfonyl chloride open-chain sulfonylated amidine intermediates were isolated and then subjected to the
cyclization step. The reaction with 2,4-dichloropyrimidine-5-sulfonyl chloride gave rise to the correspond-
ing thiadiazine-1,1-dioxides in one-pot. Similarly, a reaction of 2-chloropyridine-3-sulfonamide with
lactime ethers proceeded in one-pot readily giving the corresponding thiadiazine-1,1-dioxides. Remaining
chlorine atoms on the prepared hetaryl-annulated benzothiadiazine-1,1-dioxides readily undergo aromatic
nucleophilic displacement reactions serving thus as additional variation points for the design of biologi-
cally potent compounds.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
Cu(I)-catalyzed coupling of o-bromobenzylsulfonyl azide
with functionalized terminal acetylene and ammonium
chloride [9], and a Fe(III)-mediated cyclization of o-
bromobenzenesulfonamide with amidines [10]. However,
the transition metal-based syntheses, although successful,
have some intrinsic limitations such as moisture sensitivity
and environmental toxicity. In addition, the complicated
separation of the transition metal traces from polar reaction
products may completely prevent the use of a catalytic
protocol for the synthesis of pharmaceutical fine chemicals.
Also, ones the thiadiazine ring is constructed it is often
necessary to functionalize the system through a number of
reactions such as hydrogenation, N-alkylation or acylation,
substitution of halogens at the condensed aromatic ring, etc.
Given the drawbacks of the mentioned above synthetic routes
the development of efficient noncatalytic approaches to the
aryl-annulated thiadiazine-1,1-dioxide ring system with
acceptable options for further elaboration is necessary.
Benzo- and hetaryl-annulated thiadiazine-1,1-dioxides
are important pharmacophores with a broad range of
biological activities [1,2]. In connection with this, many
synthetic routes to the thiadiazine ring system have been
developed. These synthetic approaches can roughly be
divided into two common ones. First, noncatalytic approach
consists of the reaction of o-aminoaryl-sulfonamides with
either orthoesters [3,4] or acylating reagents [5–7]. Main
disadvantages of this approach are considerably harsh reaction
conditions (e.g., pyrolytic conditions in the case of acylating
reagents [7]) causing the formation of byproducts and a
limited availability of o-aminosulfonamides narrowing the
chemical space for drug design. The second approach to the
thiadiazine-1,1-dioxide ring involves metal-catalyzed reac-
tions, such as Friedel-Crafts ring closure of Michael adducts
of chlorosulfonyl isocyanate and aniline derivatives [8], a
© 2013 HeteroCorporation

A. Cherepakha, V. O. Kovtunenko, A. Tolmachev, and O. Lukin
Vol 000
Scheme 3. Preparation of the tricyclic pyridothiadiazine‐1,1‐dioxides from
2‐chloropyridine‐3‐sulfonamide and lactime ethers.
Analysis of the literature shows that derivatives of hetaryl-
annulated thiadiazine-1,1-dioxides, e.g., pyrido- [11–13] and
thieno- [14] thiadiazine-1,1-dioxides are often more potent
than the reference benzothiadiazine-1,1-dioxides. It is
therefore of importance to specifically focus on improving
the methods for preparation of diverse hetaryl-annulated
thiadiazine-1,1-dioxides. In this contribution efficient
noncatalytic syntheses and derivatizations of pyrido-,
pyrimido-, and thiazothiadiazine-1,1-dioxides are described.
Scheme 4. A one‐pot synthesis of pyrimidothiadiazine‐1,1‐dioxides.
RESULTS AND DISCUSSION
The synthetic pathways used to prepare the different
series of the hetaryl-annulated thiadiazine-1,1-dioxides
are illustrated in Schemes 1–7.
Pyrido[2,3-e]thiadiazine dioxides were prepared from 2-
chloropyridine-3-sulfonyl chlorides 1 or 8 and amidines
(Schemes 1 and 2).
First, sulfonyl chlorides 1 and 8 reacted with amidines in
the presence of potassium hydroxide in CH2Cl2/H2O to
give corresponding open-chain sulfonylated amidines 3,
6, and 9 in nearly quantitative yield. Amino-groups of
compounds 3a–d, 9 manifest themselves in 1H NMR
spectra recorded in DMSO as two singlets with the inten-
sity of one proton each at 7.5–9.0 ppm, whereas the
amino-group of compound 6 shows up as one broad singlet
with the intensity of two protons.
Scheme 5. An example of functionalization of chloropyridothiadiazine‐
1,1‐dioxide 15b through the nucleophilic displacement of chlorine.
Following heating of sulfonylated amidines 3 and 9 in
DMF in the presence of potassium carbonate (Schemes 1
and 2) leads to their quantitative conversion to corresponding
Scheme 6. Synthesis and functionalization of thiazothiadiazine‐1,1‐
dioxides.
Scheme 1. Preparation of the parent pyridothiadiazine-1,1-dioxides from
2-chloropyridine-3-sulfonyl chloride and amidines.
Scheme 2. Preparation of the halo-substituted pyridothiadiazine-1,1-
dioxides.
pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxides 4 and 10. Inter-
estingly, the cyclization of compound 6 required the addition
of a stronger base, sodium hydride (Scheme 1B) to give
pyridothiadiazine dioxide 7. 1H NMR spectra of the prepared
pyridothiadiazine dioxides recorded in DMSO revealed broad
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A Noncatalytic Approach to Hetaryl-Annulated 1,2,4-Thiadiazine-1,1-dioxides
Compounds 18–20 exhibited 1H NMR and LC/MS
spectral manifestations similar to those of described above
compounds 3, 4, 6, and 7.
Scheme 7. Preparation of pre‐functionalized thiazosulfonyl amidines
followed by their ring closure to thiazothiadiazine‐1,1‐dioxides.
Another interesting example illustrated in Scheme 7
constitutes reactions of sulfonylated amidine 18c with
morpholine or benzyl thiol in the presence of potassium
carbonate. In the latter case only the thiazole chlorine
displacement took place resulting in open-chain derivatives
21. Furthermore, treatment of 21a with sodium hydride
gives expected thiazothiadiazine dioxide 22 while no ring
closure occurs in the case of compound 21b.
singlets at 12–13 ppm pertaining to their 4-H protons. LC/MS
analysis of pyridothiadiazine dioxides 4, 7, and 10 showed an-
ionic mass peaks reflecting the loss of the 4-H proton.
We have recently reported a two-step synthesis of
benzothiadiazine-1,1-dioxides from 2-chlorobenzenesulfo-
namides and lactime ethers [15] consisting of a Cu(I)-
catalyzed cyclization of the open-chain sulfonyl amidine
intermediate. As illustrated in Scheme 3 a simple refluxing
of a solution of 2-chloropyridine-3-sulfonamide 11 and
lactime ether 12 in ethanol readily gives corresponding
tricyclic pyridothiadiazine dioxides 13. Notably, the reac-
tion proceeds in one-pot and requires neither a base nor
a catalyst for both bond forming steps.
Similarly, a one-pot base promoted reaction of 2,6-
dichloropyrimidine-5-sulfonyl chloride 14 with amidines
readily yields corresponding pyrimidothiazine dioxides
15 (Scheme 4). Unlike pyrido-derivatives 4, 7, and 10,
compounds 15 exhibit somewhat high N–H acidity of the
position 4 proton. Consequently, compounds 15 precipi-
tated from the reaction mixture in the form of their potassium
salts which upon workup with acetic acid (Scheme 4) gave
rise to the pure pyrimidothiadiazine-1,1-dioxides. 1H NMR
spectra of compounds 15 reveal characteristic signals of the
pyrimidine proton at 9.0-9.3 ppm as well as the NH broad
singlet at around 13.0 ppm.
CONCLUSIONS
A number of functionalized pyrido-, pyrimido-, and
thiazothiadiazine dioxides reported in this work was synthe-
sized in one or two steps under considerably mild, noncatalytic
conditions from easily accessible o-chlorohetarylsulfonyl
chlorides, amidines, and/or lactime ethers. The substitution
pattern of the thiadiazine-1,1-dioxide ring in the obtained
compounds is controlled by structural features of amidines
or lactime ethers used in the reaction. Pyrimido- and
thiazothiadiazine-1,1-dioxides offer additional variation points
represented by reactive chlorine atoms on their aromatic
heterocyclic parts.
EXPERIMENTAL
1H (500 MHz) and 13C (125 MHz) NMR spectra were
recorded on Bruker Avance DRX 500 spectrometer in
DMSO-d6 solution with TMS as an internal standard. High-
performance (HP) LC-MS analyses were done on an Agilent
1100 LCMSD SL instrument (APCI mode). Elemental analyses
were carried out on a LECO CHN-900 analyzer. The values of
elemental analyses reported herein are averages of three inde-
pendent measurements. Melting points were measured with a
Büchi melting point apparatus and are uncorrected. IR spectra
were recorded on Perkin Elmer Spectrum BX II (FT-IR) with
Pike ATP module.
As shown in Scheme 5, the chlorine atom in pyrimido
[4,5-e][1,2,4]thiadiazine-1,1-dioxides 15 is reactive enough
to undergo nucleophilic displacement reactions under rela-
tively mild conditions resulting in morpholinyl derivative
16. This is in contrast to inert halogen atoms of
pyridothiadiazine dioxides 10.
Compounds 1, 2a–d, 5, 8a, 11, 12a,b, 14, 16, and 17 were
purchased from different commercial sources (mainly Ukrorgsyntez
and Aldrich).
Reactions of 2,4-dichlorothiazol-5-sulfonyl chloride 17
with amidines 2 (Scheme 6) in the presence of potassium
hydroxide lead to open-chain sulfonylated amidines 18
which, similarly to compound 6, undergo ring closure only
if sodium hydride is used. Obtained thiazothiadiazine diox-
ides 19 readily react with nucleophiles, such as morpholine
and benzyl thiol in the presence of potassium carbonate
(Scheme 6) to give products of the chlorine displacement
in the thiazole ring 20. Interestingly, both thiadiazine ring
closure and the chlorine displacement reaction can be
carried out in one-pot. As shown in Scheme 6 an addition
of morpholine or benzyl thiol to a solution of sulfonylated
amidines 18 and potassium carbonate gives rise to
substituted thiazothiadiazine dioxides 20.
General procedure for preparation of sulfonylated
amidines 3;a–d, 6, and 9a–b.
To a stirred solution of a
pyridine-3-sulfonyl chloride (0.0236 mol) and a corresponding
amidine hydrochloride (0.0236 mol) in dichloromethane (10
mL) a concentrated water solution of potassium hydroxide
(6 mL) was added drop wise at 0°C. The reaction mixture was
allowed to stir for 8 h at room temperature. The crude product
precipitated from the reaction mixture was filtered, washed
with deionized water and dried under ambient conditions.
Then the product was dispersed in hexanes, filtered, and dried
in vacuum.
N3-[1-aminoethylidene]-2-chloro-3-pyridinesulfonamide
(3a).
NH 3368, NH2 1656, SO2 1294, 1156 cm−1; 1H NMR: d 2.16 (s, 3
H, CH3), 7.62 (m, 1 H, ArH), 8.29 (b.s., 1 H, NH), 8.41 (d, 3JHH
Colorless solid; yield 4.9 g (89 %); m.p. 126–128°C; IR:
=
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Vol 000
7 Hz, 1 H, ArH), 8.59 (d, 3JHH = 3 Hz, 1 H, ArH), 8.71 (b.s., 1 H,
NH); 13C NMR: d 22.07, 123.87, 137.91, 138.75, 147.63, 152.46,
169.45; ms (CI) m/z (%) = 234 (50) [M+1]−, 232 (100) [M-1]−, 196
(100) [M-1-HCl]+; Anal. Calcd for C7H8ClN3O2S: C 35.98, H
3.45, N 17.98. Found: C 35.93, H 3.39, N 17.62.
General procedure for preparation of 3-substituted 4H-
pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxides 4a–d and 10a,b. A
solution of sulfonylated amidine 8 (0.015 mol) and potassium
carbonate (4.15 g, 0.03 mol) in DMF (100 mL) was stirred at
80–90°C. The solvent was removed under reduced pressure and
the solid residue was dissolved in water (250 mL). The solution
was acidified with hydrochloric acid to pH 1. The precipitated
product was filtered, washed with deionized water, and dried in
vacuum.
N3-[1-amino-1-phenylmethylidene]-2-chloro-3-pyridinesulfona-
mide (3b). Colorless solid; yield 6.85 g (92%) ; m.p. 139–140°
1
C; ir : NH 3442, 3335, NH2 1623, SO2 1281, 1165 cm−1; H
3
3
NMR: d 7.50 (t, JHH = 7 Hz, 2 H, ArH), 7.61 (t, JHH = 7 Hz,
3
1 H, ArH), 7.66 (m, 1 H, ArH), 7.89 (d, JHH = 7 Hz, 2 H,
3-Methyl-4H-pyrido[2,3-e][1,2,4]thiadiazine 1,1-dioxide (4a).
Colorless solid; yield 2.78 g (94 %); m.p. 281–282°C; IR: NH 3228,
3
4
ArH), 8.45 (b.s., 1 H, NH), 8.53 (dd, JHH = 7 Hz, JHH = 1.5
Hz, 1 H, ArH), 8.63 (dd, 3JHH = 5 Hz, JHH = 1.5 Hz), 9.32 (b.
C N 1596, SO2 1282, 1140 cm−1; H NMR: d 2.36 (s, 3 H, CH3),
4
1
s., 1 H, NH); 13C NMR: d 123.91, 128.55, 129.03, 133.14,
133.49, 137.31, 139.05, 147.78, 152.76, 164.29; ms (CI) m/z
(%) = 296 (50) [M+1]−, 294 (100) [M-1]−, 258 (20) [M-1-
HCl]−; Anal. Calcd for C12H10ClN3O2S: C 48.74, H 3.41, N
14.21. Found: C 48.70, H 3.40, N 14.33.
7.52 (m, 1 H, ArH), 8.33 (d, 3JHH = 7 Hz, 1 H, ArH), 8.71 (d, 3JHH
= 1.5 Hz, 1 H, ArH), 12.68 (bs, 1 H, NH); 13C NMR: d 23.01,
117.53, 123.00, 134.22, 147.01, 153.62, 158.38; ms (CI) m/z (%) =
196 (100) [M-H]−; Anal. Calcd for C7H7N3O2S: C 42.63, H 3.58,
N 21.31. Found: C 42.60, H 3.54, N 21.32.
N3-[1-amino-1-methoxymethylidene]-2-chloro-3-pyridinesulfo-
namide (3c). Colorless solid; yield 5 g (85%); m.p. 138°C; IR:
NH 3444, 3349, 3307, NH2 1636, SO2 1289, 1151 cm−1; 1H
NMR: d 3.70 (s, 3 H, CH3), 7.45 (bs, 1 H, NH), 7.62–7.66 (m,1 H,
3-Phenyl-4H-pyrido[2,3-e][1,2,4]thiadiazine 1,1-dioxide
(4b).
Colorless solid; yield 3.77 g (97%); m.p. 275–276°C; IR:
NH 3238, C N 1598, SO2 1308, 1173 cm−1; 1H NMR: d 7.58–7.63
(m, 3 H, ArH), 7.71 (t, 3JHH = 7 Hz, 1 H, ArH), 8.05 (d, 3JHH = 7
3
3
4
ArH), 8.47 (d, JHH = 8 Hz, 1 H, ArH), 8.51 (bs, 1 H, NH), 8.61
Hz, 2 H, ArH), 8.42 (dd, JHH = 7.5, JHH = 1.5 Hz, 1 H, ArH),
8.80 (dd, 3JHH = 4.5 Hz, 4JHH = 2 Hz), 13.06 (b.s., 1 H, NH); 13C
NMR: d 118.02, 123.50, 129.21, 129.22, 131.78, 133.56, 134.29,
147.49, 153.77, 155.81; ms (CI) m/z (%) 258 (100) [M-H]−; Anal.
Calcd for C12H9N3O2S: C 55.59, H 3.50, N 16.21. Found: C 55.58,
H 3.49, N 16.25.
3
(d, JHH = 3 Hz, 1 H, ArH); 13C NMR: d 55.59, 123.83, 137.34,
147.48, 152.71, 160.96; ms (CI) m/z (%) 249 (100) M−, 251 (50)
[M+2]−; Anal. Calcd for C7H8ClN3O3S: C 33.67, H 3.23, N 16.83.
Found: C 33.65, H 3.24, N 16.82.
N3-[1-amino-1-methylsulfanylmethylidene]-2-chloro-3-pyridine-
sulfonamide (3d). Colorless solid; yield 5.45 (87 %); m.p. 113–
3-Methoxy-4H-pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxide
(4c). Colorless solid; yield 2.78 (87 %); m.p. 228–230°C; IR: NH
1
115°C; IR: NH 3358, 3270, NH2 1628, SO2 1269, 1121 cm−1; H
1
NMR: d 2.33 (s, 3 H, SCH3), 7.62–7.66 (m, 1 H, ArH), 8.24 (bs, 1
3335, C N 1597, SO2 1305, 1176 cm−1; H NMR: d 3.95 (s, 3 H,
3
4
H, NH), 8.45 (dd, JHH = 7.5 Hz, JHH = 1.5 Hz, 1 H, ArH), 8.61
(dd, 3JHH = 4.5 Hz, 4JHH = 1,5 Hz, 1 H, ArH), 8.99 (bs, 1 H, NH);
13C NMR: d 14.22, 123.81, 137.24, 139.16, 147.63, 125.75,
170.79; ms (CI) m/z (%) 228 (100) [M-HCl-1]−; Anal. Calcd for
C7H8ClN3O2S2: C 31.64, H 3.03, N 15.81. Found: C 31.64, H 3.04,
N 15.83.
OCH3), 7.44 (m, 1 H, ArH), 8.28 (m, 1H, ArH), 8.64 (m, 1 H,
ArH), 12.71 (b.s, 1 H, NH); 13C NMR: d 56.11, 117.73, 121.80,
134.01, 146.76, 153.56, 154.68; ms (CI) m/z (%) 212 (100)
[M-H]−; Anal. Calcd for C7H7N3O3S: C 39.43, H 3.31, N
19.71. Found: C 39.42, H 3.31, N 19.73.
3-Methylsulfanyl-4H-pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxide
(4d). Colorless solid; yield 3.19 g (93 %); m.p. 294–246°C; IR:
NH 3228, C N 1591, SO2 1292, 1158 cm−1; 1H NMR: d 7.50 (m, 1
N3-[1-amino-1-tetrahydro-1H-1-pyrrolylmethylidene]-2-chloro-
3-pyridinesulfonamide (6). Colorless solid; yield 5.72 g (84 %);
m.p. 136°C; IR: NH 3428, 3335, NH2 1630, SO2 1239, 1151
3
3
H, ArH), 8.33 (d, JHH = 7.5 Hz, 1 H, ArH), 8.68 (d, JHH = 3.5
Hz), 13.19 (bs, 1 H, NH); 13C NMR: d 13.89, 118.11, 122.62,
134.25, 147.34, 153.51, 162.61; ms (CI) m/z (%) 228 (100) [M-
H]−; Anal. Calcd for C7H7N3O2S2: C 36.67, H 3.08, N 18.33.
Found: C 36.66, H 3.06, N 18.32.
1
cm−1; H NMR: d 1.63–2.03 (m, 4 H, CH2), 3.13–3.47 (m, 4 H,
CH2), 7.03 (b.s., 2 H, NH), 7.57 (m, 1 H, ArH), 8.39 (d, 3JHH = 7.5
3
Hz, 1 H, ArH), 8.53 (d, JHH = 3 Hz, 1 H, ArH); 13C NMR: d
24.78, 25.50, 46.47, 47.81, 123.65, 138.72, 138.96, 147.44, 151.87,
154.71; ms (CI) m/z (%) 288 (100) M−, 290 (50) [M+2]−; Anal.
Calcd for C10H13ClN4O2S: C 41.60, H 4.54, N 19.40. Found: C
41.61, H 4.53, N 19.23.
N'-[(5-bromo-2-chloropyridin-3-yl)sulfonyl]ethanimidamide
(9a). Colorless solid; yield 6.86 g (93 %); m.p. 201–202°C; 1H
NMR: δ 2.18 (s, 3 H, CH3), 8.38 (b.s., 1 H, NH) 8.53 (s, 1 H,
ArH), 8.78 (s, 1 H, ArH), 8.81 (b.s., 1 H, NH); 13C NMR: δ
22.18, 119.35, 138.96, 140.49, 146.48, 153.09, 169.78; ms (CI)
m/z (%) = 316 (33) [M+4]−, (100) [M+2]−, 312 (67) M−; Anal.
Calcd for C7H7BrClN3O2S: C 26.90, H 2.26, N 13.44. Found: C
26.91, H 2.23, N 13.45.
7-Bromo-3-methyl-4H-pyrido[2,3-e][1,2,4]thiadiazine 1,1-dioxide
1
(10a). Colorless solid; yield 3.77 g (91 %); m.p. 273–274°C; H
NMR: δ 2.36 (s, 3 H, CH3), 8.56 (d, 4JHH = 2 Hz, 1 H, ArH), 8.82
4
(d, JHH = 2 Hz, 1 H, ArH), 12.82 (b.s, 1 H, NH); 13C NMR: δ
23.07, 116.12, 118.39, 135.96, 145.93, 154.40, 158.44; ms (CI) m/z
(%) 277 (100) [M+2-H]−, 275 (100) [M-H]−. Anal. Calcd for
C7H6BrN3O2S: C 30.45, H 2.19, N 15.22. Found: C 30.44, H 2.20,
N 15.23.
6-Chloro-3-methyl-4H-pyrido[2,3-e][1,2,4]thiadiazine-1,1-
dioxide (10b). Colorless solid; yield 3.26 g (94 %); m.p. 276–
1
3
278°C; H nrm: δ 2.34 (s, 3 H, CH3), 7.58 (d, JHH = 8 Hz, 1 H,
N'-[(2,6-dichloropyridin-3-yl)sulfonyl]ethanimidamide 9b.
Color-less solid; yield 6 g (95 %); m.p. 202–204°C; 1H NMR: δ
2.17 (s, 3 H, CH3), 7.74 (d, 3JHH = 8 Hz, 1 H, ArH), 8.35 (b.s., 1
ArH), 8.38 (d, 3JHH = 8 Hz, 1 H, ArH), 12.78 (b.s., 1 H, NH); 13
C
NMR: δ 23.11, 116.35, 123.06, 137.11, 147.52, 153.10, 158.59; ms
(CI) m/z (%) 232 (50) [M+2-H]−, 230 (100) [M-H]−; Anal. Calcd
for C7H6ClN3O2S: C 36.29, H 2.61, N 18.14. Found: C 36.30, H
2.61, N 18.11.
3-Tetrahydro-1H-1-pyrrolil-4H-pyrido[2,3-e][1,2,4]thiadiazine-
1,1-dioxide (7). A solution of compound 6 (4.32 g, 0.015 mol) in
DMF (150 mL) was added drop wise to a stirred suspension of
3
H, NH), 8.42 (d, JHH = 8 Hz, 1 H, ArH), 8.77 (b.s., 1 H, NH);
13C NMR: δ 22.01, 124.44, 137.47, 141.73, 147.17, 151.47,
169.72; ms (CI) m/z (%) = 272 (25) [M+4]−, 270 (75) [M+2]−,
268 (100) M−; Anal. Calcd for C7H7Cl2N3O2S: C 31.36, H 2.63,
N 15.67. Found: C 31.37, H 2.62, N 15.65.
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A Noncatalytic Approach to Hetaryl-Annulated 1,2,4-Thiadiazine-1,1-dioxides
sodium hydride (60% NaH suspension in oil, 1.32 g, 0.033 mol)
in dry DMF (25 mL). The reaction mixture was stirred for 5 h at
80–90°C, and then it was allowed to cool to room temperature.
The solvent was removed under reduced pressure and the solid
residue was triturated with hexanes (100 mL). Then the raw
product was filtered, dried under ambient conditions, and
dissolved in deionized water (250 mL). Acidity of the solution
was adjusted to pH 5 with hydrochloric acid causing the
precipitation of a crystalline solid. The precipitate was filtered,
washed twice with water and then with hexanes, and dried in
vacuum. Colorless solid; yield 3.60 g (95 %); m.p. 328–330°C;
General procedure for preparation of 3-substituted 6-chloro-
pyrimido[4,5-e[1,2,4]thiadiazine-1,1-dioxides (15b–d). To a
stirred solution of 2,4-dichloropyrimidine-5-sulfonyl chloride 14
(5 g, 0.02 mol) and a corresponding amidine hydrochloride
(0.02 mol) in dichloromethane (10 mL) a concentrated water
solution of potassium hydroxide (10 mL) was added drop wise at
0°C. The reaction mixture was allowed to stir at room temperature
for 8 h. A solid precipitate formed during stirring was filtered and
triturated with 50% aqueous acetic acid (50 mL). The solid
precipitate was filtered, washed with water (2 × 20 mL), and dried
in vacuum.
1
IR: NH 3447, 3387, 3300, C N 1562, SO2 1274, 1152 cm−1; H
6-Chloro-3-phenyl-4H-pyrrimido[4,5-e][1,2,4]thiadiazine-1,1-
dioxide (15b). Colorless solid; yield 3.53 g (60%); m.p. 315–
316°C (dec.); IR: NH 3215, C N 1576, SO2 1274, 1156 cm−1; 1H
NMR: d 1.78–2.04 (m, 4 H, CH2), 3.53–3.68 (m, 4 H, CH2), 7.36
(m, 1 H, ArH), 8.15 (d, 3JHH = 7 Hz, 1 H, ArH), 8.58 (d, 3JHH = 4
Hz), 11.20 (bs, 1 H, NH); 13C NMR: d 25.13, 47.76, 119.29,
120.91, 132.98, 148.28, 148.95, 152.18; ms (CI) m/z (%) 251
(100) [M-H]−; Anal. Calcd for C10H12N4O2S: C 47.61, H 4.79, N
22.21. Found: C 47.60, H 4.81, N 22.21.
General procedure for preparation of pyrido[2,3-e][1,2,4]
thiadiazine-1,1-dioxides 13. A solution of 2-chloropyridine-
3-sulfonamide 11 (5 g, 0.026 mol) and a corresponding lactime
ether 12 (0.08 mol) in ethanol was heated at reflux for 8 h.
Then the reaction mixture was allowed to cool to room
temperature. The solvent was removed under reduced pressure.
The solid residue was triturated with deionized water (50 mL),
filtered, and washed with water (2 × 20 mL).
3
3
NMR: d 7.62 (t, JHH = 7.5 Hz, 2 H, ArH), 7.74 (t, JHH = 7.5
3
Hz, 1 H, ArH), 8.12 (d, JHH = 7.5 Hz, 1 H, ArH), 9.30 (s, 1 H,
ArH), 12.281 (bs, 1 H, NH); 13C NMR: d 115.33, 129.34,
129.40, 131.23, 134.12, 155.98, 156.29, 158.64, 162.00; ms (CI)
m/z (%) 295 (50) [M-H+2]−, 293 (100) [M-H]+; Anal. Calcd for
C11H7ClN4O2S: C 44.83, H 2.39, N 19.01. Found: C 44.82, H
2.40, N 19.04.
6-Chloro-3-methoxy-4H-pyrrimido[4,5-e][1,2,4]thiadiazine-1,1-
dioxide (15c). Colorless solid; yield 1.6 g (32%); m.p. 194–196°C
(dec); IR: C N 1583, SO2 1277, 1151 cm−1; 1H NMR: d 3.96 (s, 3 H,
OCH3), 9.21 (s, 1 H, ArH), 13.56 (bs, 1 H, NH); 13C NMR: d 56.78,
115.45, 154.12, 155.51, 157.61, 162.03; ms (CI) m/z (%) 249 (50)
[M-H+2]−, 247 (100) [M-H]−; Anal. Calcd for C6H5ClN4O3S: C
28.98, H 2.03, N 22.53. Found: C 28.98, H 2.02, N 22.49.
6-Chloro-3-methylsulfanyl-4H-pyrimido[4,5-e][1,2,4]thiadiazine-
1,1-dioxide (15d). Colorless solid; yield 2.28 g (43%); m.p.
191–192°C (dec); IR: NH 3414, 3330, C N 1584, SO2 1297,
8,9-Dihydro-7H-pyrido[2,3-e]pyrrolo[2,1-c][1,2,4]thiadiazine
5,5-dioxide (13a).
Colorless solid; yield 5.68 g (98%); m.p.
1
226–228°C; IR: C N 1576, SO2 1296, 1170 cm−1; H NMR: d
2.185 (m, 2 H, CH2), 3.04 (m, 2 H, CH2), 4.23 (m, 2 H, CH2),
3
7.57 (m, 1 H, ArH), 8.38 (d, JHH = 7.5 Hz, 1 H, ArH), 7.76 (s,
1147 cm−1 1H NMR: d 2.77 (s, 3 H, SCH3), 9.00 (s, 1 H,
;
1 H, ArH); 13C NMR: d 18.16, 34.09, 49.53, 117.80, 122.75,
134.49, 145.64, 153.26, 164.01; ms (CI) m/z (%) 223 (100) M+;
Anal. Calcd for C9H9N3O2S: C 48.42, H 4.06, N 18.82. Found:
C 48.41, H 4.07, N 18.65.
ArH), 13.71 (bs, NH); 13C NMR: d 14.08, 115.59, 155.19,
158.17, 161.93, 163.50; ms (CI) m/z (%) 265 (50) [M-H+2]+,
263 (100) [M-H]+; Anal. Calcd for C6H5ClN4O2S2: C 27.22, H
1.90, N 21.17. Found: C 27.24, H 1.89, N 21.20.
8,9,10,11-Tetrahydro-7H-pyrido[2',3':5,6][1,2,4]thiadiazino
[4,3-a]azipine-5,5-dioxide (13b). Colorless solid; yield 6.46 g
6-Morpholine-4-yl-3-phenyl-4H-pyrimido[4,5-e][1,2,4]thiadiazine-
1,1-dioxide (16). A stirred solution of 15b (2.94 g, 0.01 mol),
morpholine (0.95 g, 0.011 mol), and potassium carbonate (2.76 g,
0.02 mol) in DMF (50 mL) was heated at 100°C for 8 h. Then the
solvent was removed under reduced pressure. The solid residue was
dissolved in water and the solution was acidified with concentrated
hydrochloric acid to pH 6. The precipitated crystalline powder was
filtered, washed with water, and dried in vacuum. Colorless solid;
(99%); m.p. 172°C; IR: C N 1575, SO2 1298, 1175 cm−1 1H
;
NMR: d 1.57–1.96 (m, 6 H, CH2), 2.92–3.08 (m, 2 H, CH2),
3
4.48–4.67 (m, 2 H, CH2), 7.59 (m, 1 H, ArH), 8.39 (d, JHH
=
5.5 Hz, 1 H, ArH), 8.81 (s, 1 H, ArH); 13C NMR: d 24.48,
27.02, 28.24, 38.23, 45.84, 118.92, 122.66, 134.79, 147.30,
152.92, 165.47; ms (CI) m/z (%) 251 (100) M+; Anal. Calcd for
C11H13N3O2S: C 52.57, H 5.21, N 16.72. Found: C 52.48, H
5.20, N 16.73.
1
yield 3.24 g (97%); m.p. 305–307°C (dec); H NMR: d 3.70 (s, 4
3-Methyl-4H-pyrimido[4,5-e][1,2,4]thiadiazine-1,1-dioxide
H, CH2), 3.87 (s, 4 H, CH2), 7.59 (s, 2 H, ArH), 7.68 (s, 1 H,
ArH), 8.04 (s, 2 H, ArH), 8.68 (s, 1 H, ArH), 12.524 (bs, 1 H,
NH); 13C NMR: d 44.65, 66.34, 106,02, 129.15, 132.08, 133.47,
154.99, 156.15, 156.67, 156.69, 161.12; ms (CI) m/z (%) 344 (100)
[M-H]−; Anal. Calcd for C15H15N5O3S: C 52.17, H 4.34, N 20.28.
Found: C 52.15, H 4.33, N 20.41.
(15a).
To a stirred solution of 2,4-dichloropyrimidine-5-
sulfonyl chloride 14 (5 g, 0.02 mol) and methylamidine
hydrochloride 2a (1.91 g, 0.02 mol) in dichloromethane (10
mL) a concentrated water solution of potassium hydroxide (10
mL) was added drop wise at 0°C. The reaction mixture was
allowed to stir at room temperature for 8 h. The aqueous layer
was separated and acidified with 50% aqueous acetic acid to pH
5. The solution was extracted with dichloromethane (3 × 50
mL). Dichloromethane layers were combined, dried over
magnesium sulfate, and evaporated to give 0.28 g (6%) of 15a,
General procedure for preparation of sulfonylated amidines
(18).
To a stirred solution of 2,6-dichlorothiazole-5-sulfonyl
chloride 17 (5 g, 0.02 mol) and a corresponding amidine
hydrochloride (0.02 mol) in toluene (10 mL) a concentrated water
solution of potassium carbonate (10mL) was added drop wise at
0°C. The reaction mixture was allowed to stir at room temperature
for 8 h. The crude product precipitated during stirring was filtered,
washed with water and then upon drying with hexanes, and dried
in vacuum.
1
as yellow solid; m.p. 293–294°C (dec); H NMR: d 2.37 (s, 3
H, CH3), 9.29 (s, 1 H, ArH), 13.34 (bs, 1 H, NH); 13C NMR: d
23.31, 114.89, 155.11, 158.56, 159.29, 161.89; ms (CI) m/z (%)
233 (50) [M-H+2]−, 231 (100) [M-H]+; Anal. Calcd for
C6H5ClN4O2S: C 30.98, H 2.17, N 24.08. Found: C 30.97, H
2.18, N 24.07.
N'-[(2,4-dichlorothiazolo-5-yl)sulfonyl]ethanimidamide
(18a). Colorless solid; yield 4.66 g (85%); m.p. 177–179°C; IR:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Cherepakha, V. O. Kovtunenko, A. Tolmachev, and O. Lukin
Vol 000
NH 3340, 3150, NH2 1674, C N 1540, SO2 1213, 1135 cm−1; H
NMR: δ 2.21 (s, 3 H, CH3), 8.59 (b.s., 1 H, NH), 8.94 (b.s., 1 H,
NH); 13C NMR: δ 21.52, 135.65, 136.69, 153.16, 170.27; ms (CI)
m/z (%) 277 (25) [M+4]−, 275 (75) [M+2]−, 273 (100) M−; Anal.
Calcd for C5H5Cl2N3O2S2: C 21.91, H 1.84, N 15.33. Found: C
21.89, H 1.83, N 15.31.
CH2), 3.26–3.40 (m, 4 H, CH2), 12.00 (b.s., 1 H, NH); 13C NMR:
δ 25.33, 47.70, 60.80, 147.23, 148.97, 155.50; ms (CI) m/z (%) 293
(50) [M+2-H]+, 291 (100) [M-1]+; Anal. Calcd for C8H9ClN4O2S2:
C 32,82, H 3,10, N 19,14. Found: C 32,80, H 3,11, N 19,16.
1
General procedure for preparation of 3,6-disubstituted 4H-
[1], [3]thiazolo[4,5-e][1,2,4]thiadiazine-1,1-dioxides 20a–d
from sulfonylated amidines 18a,b. To a stirred solution of a
corresponding sulfonylated amidine 18a,b (0.02 mol) and
potassium carbonate (2.76 g, 0.02 mol) in DMF (50 mL) a
solution of morpholine or benzyl thiol (0.02 mol) in DMF (50
mL) was added. The reaction mixture was stirred at 80°C for
8 h. The solvent was removed under reduced pressure. The
solid residue was dissolved in water (100 mL). Concentrated
hydrochloric acid was added to the solution to adjust to pH 6.
The precipitated crude product was filtered, washed with water
(2 × 50 mL), recrystallized from ethanol, and dried in vacuum.
Preparation of 6-morpholin-4-yl-3-phenyl-4H-[1,3]thiazolo
N'-[(2,4-dichloro-1,3-thiazolo-5-yl)sulfonyl]benzencarboximidamide
(18b). Colorless solid; yield 6.18 g (92%); m.p. 97–98°C; IR: NH
3409, 3321, NH2 1643, C N 1535, SO2 1244, 1126 cm−1; 1H NMR: δ
7.55 (t, 3JHH = 7 Hz, 2 H, ArH), 7.66 (t, 3JHH = 7 Hz, 1 H, ArH), 7.94
3
(d, JHH = 7 Hz, 2 H, ArH), 9.05 (b.s., 2 H, NH); 13C NMR: δ
128.69, 129.12, 132.99, 133.44, 135.98, 136.21, 153.54, 164.40;
MS (CI) m/z (%) 340 (25) [M+4]−, 338 (75) [M+2]−, 336 (100)
M−. Anal. Calcd for C10H7Cl2N3O2S2: C 35.72, H 2.10, N 12.50.
Found: C 35.74, H 2.09, N 12.51.
N′-[(2,4-dichloro-1,3-thiazolo-5-yl)sulfonyl]pyrrolidine-1-
carboximidamide (18c). Colorless solid; yield 5.72 g (87%); m.
p. 151°C; IR: NH 3451, 3354, NH2 1660, C N 1566, SO2 1237, 1133
cm−1; 1H NMR: δ 1.75–1.98 (m, 4 H, CH), 3.28–3.50 (m, 4 H, CH),
7.10 (b.s., 2 H, NH); 13C NMR: δ 24.75, 25.45, 46.68, 48.08, 134.71,
137.98, 152.13, 154.34; MS (CI) : m/z (%) = 332 (25) [M+4]−, 330
(75) [M+2]−, 328 (100) M+; Anal. Calcd for C8H10Cl2N4O2S2: C
29.19, H 3.06, N 17.02. Found: C 29.17, H 3.06, N 17.05.
[4,5-e][1,2,4]thiadiazine-1,1-dioxide (20c) from 19b.
To a
stirred solution of 19b (1.5 g, 0.005 mol) and potassium
carbonate (1.38 g, 0.01 mol) in DMF (50 mL) a solution of
morpholine (0.87 g, 0.01 mol) in DMF (50 mL) was added. The
reaction mixture was stirred at 80°C for 16 h. The solvent was
removed under reduced pressure. The solid residue was
dissolved in water (100 mL). Concentrated hydrochloric acid
was added to the solution to adjust to pH 6. The precipitated
crude product was filtered, washed with water (2 × 50 mL),
recrystallized from ethanol, and dried in vacuum.
3-Methyl-6-morpholin-4-yl-4H-[1,3]thiazolo[4,5-e][1,2,4]
thiadiazine-1,1-dioxide (20a). Colorless solid; yield 5 g (87%); m.
p. 353–355°C; IR: NH 3230, C N 1572, SO2 1259, 1158 cm−1; 1H
NMR: δ 2.25 (s, 3 H, CH3), 3.52 (s, 4 H, CH2), 3.74 (s, 4 H, CH2),
12.74 (b.s., 1 H, NH); 13C NMR: δ 22.06, 48.46, 65.63, 96.02,
149.19, 155.03, 170.63; ms (CI) m/z (%) = 287 (100) [M-H]−;
Anal. Calcd for C9H12N4O3S2: C 37.49, H 4.19, N 19.43. Found: C
37.51, H 4.20, N 19.47.
6-(Benzylsulfanyl)-3-methyl-4H-[1,3]thiazolo[4,5-e][1,2,4]
thiadiazine-1,1-dioxide (20b). This compound was obtained
as yellow solid; yield 5.33 g (82%); m.p. >360°C; IR: NH 3196,
C N 1572, SO2 1284, 1156 cm−1; 1H NMR: δ 2.32 (s, 3 H, CH3),
4.63 (s, 2 H, CH2), 7.33 (t, 3JHH = 7 Hz, 1 H, ArH), 7.39 (t, 3JHH = 7
Hz, 2 H, ArH), 7.52 (d, 3JHH = 7 Hz, 2 H, ArH), 13.28 (b.s., 1 H,
NH); 13C NMR: δ 22.08, 37.92, 128.40, 129.19, 129.56, 136.05,
149.93, 155.66, 171.09; ms (CI) m/z (%) = 324 (100) [M-H]−;
Anal. Calcd for C12H11N3O2S3: C 44.29, H 3.42, N 12.91. Found:
C 44.28, H 3.44, N 12.91.
6-Chloro-3-methyl-4H-[1,3]thiazolo[4,5-e][1,2,4]thiadiazine-
1,1-dioxide (19a). To a suspension of sodium hydride (60% NaH
in oil, 0.44 g, 0.011 mol) in dry DMF (10 mL) a solution of 17a (2.74
g, 0.01 mol) in dry DMF (100 mL) was added drop wise. The reaction
mixture was allowed to stir at room temperature for 16 h. The solvent
was removed under reduced pressure. The solid residue was dissolved
in water (100 mL) and the solution was extracted with hexanes to
remove traces of oil. Aqueous layer was separated and extracted
with dichloromethane (3 × 50 mL). Dichloromethane layers were
combined, dried over magnesium sulfate, and evaporated to give
1
0.4 g (17%) of 19a, as yellow solid; m.p. 205–206°C (dec); H
NMR: δ 2.33 (s, 3 H, CH3), 13.47 (b.s., 1 H, NH); 13C NMR: δ
22.22, 110.21, 148.54, 156.11, 156.92; ms (CI) m/z (%) 238 (50)
[M+2-H]−, 236 (100) [M-H]−; Anal. Calcd for C5H4ClN3O2S2: C
25.27, H 1.70, N 17.68. Found: C 25.26, H 1.70, N 17.69.
General procedure for cyclization of sulfonylated amidines
21b–c to 3-substituted 6-chloro-4H-thiazo[4,5-e][1,2,4]thiadiazine-
1,1-dioxides 19b–c.
To a suspension of sodium hydride (60%
NaH in oil, 0.44 g, 0.011 mol) in dry DMF (10 mL) a solution of a
corresponding sulfonylated amidine 17 (0.01 mol) in dry DMF
(100 mL) was added drop wise. The reaction mixture was allowed
to stir at room temperature for 16 h. The solvent was removed
under reduced pressure. The solid residue was dissolved in water
(100 mL). Concentrated hydrochloric acid was added to the
solution to adjust to pH 3. The precipitated crude product
was filtered, washed with water (2 × 25 mL) and then with hexanes
(3 × 50 mL), and dried in vacuum.
6-Morpholin-4-yl-3-phenyl-4H-[1,3]thiazolo[4,5-e][1,2,4]
thiadiazine-1,1-dioxide (20c). Colorless solid; yield 6.37 g (91%);
m.p. >360°C; IR: NH 3456, C N 1590, SO2 1270, 1158 cm−1.; 1H
NMR: δ 3.53 (m, 4 H, CH2), 3.77 (m, 4 H, CH2), 7.38–7.53 (m, 3
3
H, ArH), 8.14 (d, JHH = 8 Hz, 2 H, ArH); 13C NMR: δ 48.48,
6-Chloro-3-phenyl-4H-[1,3]thiazolo[4,5-e][1,2,4]thiadiazine-
65.83, 96.89, 128.32, 128.52, 130.96, 136.55, 152.00, 155.52,
169.25; ms (CI) m/z (%) = 349 (100) [M-H]−; Anal. Calcd for
C14H14N4O3S: C 47.99, H 4.03, N 15.99. Found: C 48.02, H 4.02,
N 16.00.
1,1-dioxide (19b).
Colorless solid; yield 2.19 g (73%); m.p.
312–314°C (dec); IR: NH 3217, C N 1599, SO2 1281, 1161
cm−1; 1H NMR: δ 7.62 (d, 3JHH = 7 Hz, 2 H, ArH), 7.71 (t, 3JHH
3
= 7 Hz, 1 H, ArH), 8.06 (d, JHH = 7 Hz, 2 H, ArH), 13.86 (b.s.,
6-(Benzylsulfanyl)-3-phenyl-4H-[1,3]thiazolo[4,5-e][1,2,4]
1 H, NH); 13C NMR: δ 111.18, 128.98, 129.37, 131.13, 133.56,
149.13, 153.64, 157.04; ms (CI) m/z (%) 300 (50) [M+2-H]+, 298
(100) [M-H]+; Anal. Calcd for C10H6ClN3O2S2: C 40.07, H 2.02,
N 14.02. Found: C 40.09, H 2.01, N 14.00.
thiadiazine-1,1-dioxide (20d).
This compound was obtained as
1
yellow solid; yield 6.5 g (84%); m.p. >360°C; H NMR: δ 4.67
3
3
(s, 2 H, CH2), 7.33 (t, JHH = 7 Hz, 1 H, ArH), 7.40 (t, JHH = 7
Hz, 2 H, ArH), 7.54 (d, 3JHH = 7 Hz, 2 H, ArH), 7.61 (t, 3JHH = 7
3
3
6-Chloro-3-pyrrolidin-1-yl-4H-[1,3]thiazolo[4,5-e][1,2,4]
Hz, 2 H, ArH), 7.70 (t, JHH = 7 Hz), 8.05 (d, JHH = 7 Hz, 2 H,
ArH), 13.69 (b.s., 1 H, NH); 13C NMR (125 MHz, DMSO-d6): δ =
37.93, 107.97, 128.46, 128.97, 129.23, 129.34, 129.66, 131.19,
thiadiazine-1,1-dioxide (19c).
Colorless solid; yield 1.05 g
(36%); m.p. 256–257°C (dec); 1H NMR: δ 1.73–2.08 (m, 4 H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
A Noncatalytic Approach to Hetaryl-Annulated 1,2,4-Thiadiazine-1,1-dioxides
133.44, 135.99, 150.47, 153.34, 171.43; ms (CI) m/z (%) 386 (100)
[M-H]−; Anal. Calcd for C17H13N3O2S3: C 52.69, H 3.38, N 10.84.
Found: C 52.70, H 3.37, N 10.87.
8 h. The solvent was removed under reduced pressure. The solid
residue was dissolved in water (100 mL). Concentrated
hydrochloric acid was added to the solution to adjust to pH 5.
The precipitated crude product was filtered, washed with water
(3 × 50 mL) and then with hexanes, recrystallized from ethanol,
and dried in vacuum. Colorless solid; yield 1.42 g (83%); m.p.
N′-[(4-chloro-2-morpholin-4-yl-1,3-thiazole-5-yl)sulfonyl]
pyrrolidine-1-carboximidamide (21a). To a stirred solution of 18c
(3.3 g, 0.01 mol) and potassium carbonate (2.76 g, 0.02 mol) in DMF
(50 mL) a solution of morpholine (0.87 g, 0.01 mol) in DMF (50 mL)
was added. The reaction mixture was stirred at 80°C for 16 h. The
solvent was removed under reduced pressure. The solid residue was
dissolved in water (100 mL). The precipitated crude product was
filtered, washed with 20% water solution of potassium hydroxide
(50 mL) and then with water (2 × 50 mL), and dried in vacuum.
Colorless solid; yield 3.3 g (87%); m.p. 234–235°C; IR: NH 3437,
1
293–294°C; H NMR: δ 1.93 (s, 4 H, CH2), 3.48 (s, 4 H, CH2),
3.53 (s, 4 H, CH2), 3.76 (s, 4 H, CH2), 11.02 (b.s, 1 H, NH); 13C
NMR: δ 25.22, 47.58, 48.36, 65.68, 94.56, 147.27, 149.33, 170.58;
ms (CI) m/z (%) 344 (100) [M-H]−; Anal. Calcd for C12H17N5O3S2:
C 41.97, H 4.99, N 20.39. Found: C 42.00, H 4.98, N 20.40.
1
3229, 1604, C N 1550, SO2 1269, 1149; H NMR: δ 1.73–2.016
REFERENCES AND NOTES
(m, 4 H, CH2), 3.24–3.32 (m, 4 H, CH2), 3.38–3.46 (m, 4 H, CH2),
3.65–3.77 (m, 4 H, CH2), 7.03 (b.s., 2 H, NH); 13C NMR: δ 25.21,
46.46, 47.58, 65.64, 120.75, 135.02, 154.49, 168.11, 170.54;
ms (CI) m/z (%) 381 (50) [M+2]−, 379 (100) M−; Anal. Calcd
for C12H18ClN5O3S2: C 37.94, H 4.78, N 18.44. Found: C 37.96,
H 4.79, N 18.41.
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[3] Gilow, H. M.; Jacobus, J. J Org Chem 1963, 28, 1994.
[4] Francotte, P.; de Tullio, P.; Goffin, E.; Dinitilhac, G.;
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[5] Girad, Y.; Atkinson, J. J Med Chem 1982, 25, 113.
[6] Makino, S.; Okuzumi, T.; Nakanishi, T.; Tsuji, T. Tetrahedron
Lett 2002, 43, 8401.
[7] Yale, H. L.; Losee, K.; Bernstein, J. J Am Chem Soc 1960, 82, 2042.
[8] Girad, Y.; Atkinson, J. G.; Rokach, J. J Chem Soc Perkin
Trans 1 1979, 1043.
[9] Kim, J.; Lee, S. Y.; Lee, J.; Do, Y.; Chang, S. J Org Chem
2008, 73, 9454.
N′-([2-(benzylthio)-4-chloro-1,3-thiazol-5-yl]sulfonyl)pyrrolidine-
1-carboximidamide (21b). To a stirred solution of 18c (3.3 g, 0.01
mol) and potassium carbonate (2.76 g, 0.02 mol) in DMF (50 mL) a
solution of benzyl thiol (1.24 g, 0.01 mol) in DMF (50 mL) was
added. The reaction mixture was stirred at 80°C for 8 h. The solvent
was removed under reduced pressure. The solid residue was
dissolved in water (100 mL). Concentrated hydrochloric acid was
added to the solution to adjust to pH 6. The precipitated crude
product was filtered, washed with water (2 × 50 mL), recrystallized
from methanol, and dried in vacuum. Colorless solid; yield 3.05 g
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1
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(73%) ; m.p. 256–257°C; H NMR: δ 1.67–2.106 (m, 4 H, CH2),
3.26–3.31 (m, 4 H, CH2), 4.54 (s, 2 H, PhCH2S), 7.09 (b.s., 2 H,
3
3
NH), 7.32 (t, JHH = 7 Hz, 1 H, ArH), 7.38 (t, JHH = 7 Hz, 2 H,
ArH), 7.47 (d, 3JHH = 7 Hz, 2 H, ArH); 13C NMR: δ 24.82, 25.50,
37.71, 46.56, 47.94, 128.31, 129.13, 129.56, 134.12, 136.15, 154.36,
166.64; ms (CI) m/z (%) 418 (50) [M+2]−, 416 (100) M−; Anal.
Calcd for C15H17ClN4O2S3: C 43.21, H 4.11, N 13.44. Found: C
43.22, H 4.10, N 13.42.
6-Morpholin-4-yl-3-pyrrolidin-1-yl-4H-[1,3]thiazolo[4,5-e]
[1,2,4]thiadiazine-1,1-dioxide (22a). To a stirred suspension of
sodium hydride (60% NaH in oil, 0.24 g, 0.006 mol) in dry DMF
(10 mL) a solution of 21a (1.9 g, 0.005 mol) in dry DMF (50 mL)
was added drop wise. The reaction mixture was stirred at 50°C for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet