Efficient syntheses of 1,2,3,4,4a,5-hexahydro-pyrazino[2,1-c][1,4]benzothiazine-6,6-dioxide

Article abstract of DOI:10.1016/j.tet.2010.01.092

Expeditious routes to 1,2,3,4,4a,5-hexahydro-pyrazino[2,1-c][1,4]benzothiazine-6,6-dioxide, a methylenesulfone-constrained arylpiperazine, have been developed. The key step forms the tricyclic system in a cascade of reactions via a 1,4-addition, nitrogen alkylation, and aromatic substitution sequence.

Full text of DOI:10.1016/j.tet.2010.01.092

Tetrahedron 66 (2010) 2273–2276
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient syntheses of 1,2,3,4,4a,5-hexahydro-pyrazino[2,1-c][1,4]-
benzothiazine-6,6-dioxide
,
b
Ronald C. Bernotas a , Rebecca J. Dooley
*
a Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426 USA
b Discovery Analytical Chemistry, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426 USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Expeditious routes to 1,2,3,4,4a,5-hexahydro-pyrazino[2,1-c][1,4]benzothiazine-6,6-dioxide, a methyl-
enesulfone-constrained arylpiperazine, have been developed. The key step forms the tricyclic system
in a cascade of reactions via a 1,4-addition, nitrogen alkylation, and aromatic substitution sequence.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 December 2009
Received in revised form
25 January 2010
Accepted 26 January 2010
Available online 1 February 2010
Keywords:
Arylpiperazine
Cascade reaction
Sulfones
Aromatic substitution
1. Introduction
Our approach to 4 was based on a key cascade of several steps,
reacting a two nucleophile component with an electrophile in-
1-Arylpiperazines constitute one of the largest classes of G-pro-
tein-coupled receptors (GPCRs).1 Constrained analogs in which the
piperazine and aromatic rings are connected by a two-atom linker
have been targeted as potentially more selective or higher affinity
ligands for GPCRs (Fig. 1). These two-atom linkers have included
ethylene (1),2a amide (2),2b aminomethylene (3),2c and sulfonyl-
methylene groups (4).2d The last constrained system was especially
intriguing as it was incorporated into larger molecules as potential
serotonergicligands.Thereportedpreparationof4involvedalengthy,
stepwise introduction of the second and third rings. A continuing
interest in constrained arylpiperazines led us to investigate other
approaches to the 1,2,3,4,4a,5-hexahydro-pyrazino[2,1-c][1,4]benzo-
thiazine-6,6-dioxide system. We report here efficient syntheses,
which incorporate reaction cascades to form tricyclic 4.
corporating three reactive positions (Fig. 2). Retrosynthetically, 4
would arise from a 1-(arylsulfonyl)-3-chloro-1-propene, which
incorporated three electrophilic centers: an
a,b-unsaturated sul-
fone, an allylic chloride, and an ortho-halogenated arylsulfone.
Reaction of ethylenediamine with such an arylsulfone should result
in sequential addition of one nitrogen to the a,b-unsaturated sul-
fone (step a), then displacement of the chloride by the second
amine to form a piperazine (step b), and finally intramolecular
substitution of the halogen ortho to the sulfone on the aromatic ring
by the first nitrogen (step c) completing the tricyclic system. The
addition of amines to a,b-unsaturated sulfones is a facile reaction
and would likely occur first.3 It was anticipated that the intra-
molecular nature of the second and third steps would accelerate
these reactions thus limiting potential intermolecular side re-
actions. 1-(Arylsulfonyl)-3-chloro-1-propenes can be synthesized
directly from 3-(arylsulfonyl)-1-propenes by palladium-catalyzed
Figure 1. Examples of constrained 1-arylpiperazines.
* Corresponding author.
E-mail address: bernotron@comcast.net (R.C. Bernotas).
Figure 2. Retrosynthetic analysis.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.092

2274
R.C. Bernotas, R.J. Dooley / Tetrahedron 66 (2010) 2273–2276
oxidative halogenation6 and the latter propenes can, in turn, be
accessed from commercially available arylsulfonyl chlorides.
approaches. The key reactions involved multistep cascades to form
the tricyclic structure.
2. Results and discussion
4. Experimental
A short synthesis of key intermediate 7 was targeted for the prep-
aration of 4 (Scheme 1). Requisite 3-(arylsulfonyl)-1-propene 6a was
made in one pot by sodium sulfite-mediated reduction of arylsulfonyl
chloride 5a to the corresponding sulfinic acid followed by two-phase
alkylation with allyl bromide in the presence of a phase-transfer cat-
alyst.4 We have used a similar one pot approach to synthesize chlor-
omethylarylsulfones using bromochloromethane in place of allyl
bromide.5 Using this process, fluoro analog 6b was also prepared
reasoning that fluorine might be more readily displaced in a sub-
sequent intramolecular aromatic substitution. Conversion of sulfone
6a into arylsulfone 7 was accomplished in one-step following the
procedure of Ogura6 by heating with CuCl2, catalytic PdCl2, and NaCl in
acetic acid. Unfortunately, even on prolonged heating, 7 was accom-
panied by significant amounts of 6a and separation of the two com-
pounds was difficult. However, a portion of purified 7 was obtained
from the mixture and used in the key cyclization reaction proposed in
Figure 2. Heating 7 with three equivalents of ethylenediamine in 2-
ethoxyethanol for 48 h gave the desired tricyclic 4 in good yield (71%)
after converting the purified free amine to the hydrochloride salt.
4.1. General procedures
General experimental: Solvents and chemicals were pur-
chased from VWR, Oakwood, and Aldrich Chemical Co. and used
without further purification. Melting points were obtained on
a Thomas–Hoover melting point apparatus and are uncorrected.
Chromatography was performed on silica gel, typically using an
ISCO Companion. High-resolution mass spectra were typically
obtained on a Waters LC-TOFMS instrument and were measured
to within 5 ppm of calculated values. 1H, 13C, and 19F NMR spectra
were acquired on Bruker DPX (300 MHz), Varian INOVA
(400 MHz), and/or Bruker AVANCE II (600 MHz) spectrometers.
All 2D NMR data for 4 were acquired on a Bruker AVANCE II
600 MHz NMR spectrometer with a 1.7 mm inverse triple reso-
nance cryoprobe (TCI 1H/13C/15N). NMR data are given as delta
values (
internal reference (
¼0 ppm), as appropriate. For the NMR data peak descriptions
app means apparent and br means broad.
d
) in parts per million, using tetramethylsilane as an
d
¼0 ppm) or CFCl3 as an external reference
(
d
Scheme 1. Reagents and conditions: (a) Na2SO3 (1.87 equiv), NaHCO3 (2.0 equiv), H2O, 100 ꢀC, 1.5 h, then (n-Bu)4NBr (cat), allyl bromide, 75 ꢀC, 16 h; (b) CuCl2 (6 equiv), PdCl2
(0.03 equiv), NaCl (13 equiv), AcOH, 80 ꢀC, 2 d; (c) H2NCH2CH2NH2 (3–4 equiv), EtOCH2CH2OH (0.1 M), 130–135 ꢀC, 24–48 h; (d) Br2 (1.1 equiv), CH2Cl2, 3–4 h, rt.
The success of this strategy for an efficient preparation of tricyclic
4 led us to seek an alternative sequence avoiding the palladium-
catalyzed oxidative rearrangement. One approach would be to con-
vert alkene 6a to the corresponding dibromide 8a and subject the
dibromide to ethylenediamine as above to effect a cascade of two
amine displacements of the two bromides followed by intra-
molecular aromatic substitution reaction to form the tricyclic system.
Bromination of 6a afforded 8a in essentially quantitative yield as
anticipated from literature precedent.7 Refluxing 8a with four
equivalents of ethylenediamine for 48 h afforded 4 directly in
a comparable yield to that obtained with 7. Since treatment of
dibromides like 8a with amines is known to cause elimination to the
4.2. Syntheses
4.2.1. 1-(Allylsulfonyl)-2-chlorobenzene (6a). Compound 5a (2.12 g,
10.0 mmol) was treated with a slurry of Na2SO3 (2.35 g, 18.7 mmol)
and NaHCO3 (1.68 g, 20 mmol) in water (12 mL). The stirred mixture
was heated at 100 ꢀC for 1.5 h, then cooled, and treated with tetra-
butylammonium bromide (0.200 g, 0.62 mmol) and allyl bromide
(4.25 mL, 50 mmol). The mixture was heated at 70 ꢀC for 6 h. The
cooled reaction was treated with water (4 mL) and extracted with
dichloromethane (2ꢁ15 mL). The extracts were dried (MgSO4),
concentrated in vacuo and chromatographed on silica gel using
25:75 ethyl acetate/hexanes to afford 6a as a colorless oil (2.03 g,
bromoanalogof
a,b-unsaturatedsulfone7, cyclizationlikelyproceeds
94%).1H NMR(CDCl3, 400 MHz):
d 8.07 (1H, app dt, J 1.1, 7.4 Hz), 7.59–
by an initial elimination to the
a
,
b
-unsaturated sulfone followed by
7.54 (2H), 7.46 (1H, m), 5.74 (1H, m), 5.30 (1H, d with fine coupling, J
10.3 Hz), 5.25 (1H, dd, J 1.1, 18.2 Hz), 4.16 (2H, dd, J 1.0, 7.4 Hz) ppm;
asimilarcascade tothatpostulatedearlier(Fig. 2).8 Compound 8b, the
ortho-fluoro analog of 8a, was prepared as described above from the
allylsulfone (6b) because the fluorine should be more readily dis-
placed in the aromatic substitution reaction. Cyclization of 8b was
essentially complete within 24 h and provided 4 in 68% yield. Struc-
tural integrity of 4 was confirmed by full NMR assignment.9
13C NMR (CDCl3):
d 135.9.134.7,132.6,132.2,131.7,127.3,124.9,124.2,
58.7 ppm; MS (ESþ): 216.9 (MþH); HRMS: calcd for C9H9ClO2SþHþ,
217.0084; found (ESI, [MþH]þ), 217.0095. HPLC purity¼100%.
4.2.2. 1-(Allylsulfonyl)-2-fluorobenzene (6b). Compound 5b (5.84 g,
30.0 mmol) was treated with a slurry of Na2SO3 (7.06 g, 56.0 mmol)
and NaHCO3 (5.04 g, 60 mmol) in water (40 mL). The stirred mix-
ture was heated at 100–105 ꢀC for 1.5 h, then cooled, and treated
with tetrabutylammonium bromide (0.064 g, 0.20 mmol) and allyl
bromide (13.0 mL, 150 mmol). The mixture was heated at 70 ꢀC for
3. Conclusion
In summary, 1,2,3,4,4a,5-hexahydro-pyrazino[2,1-c][1,4]benzo-
thiazine-6,6-dioxide was efficiently prepared by two related

R.C. Bernotas, R.J. Dooley / Tetrahedron 66 (2010) 2273–2276
2275
16 h. The cooled reaction was treated with water (20 mL) and
extracted with dichloromethane (3ꢁ20 mL). The extracts were
dried (MgSO4), concentrated in vacuo and chromatographed on
silica gel using a 0:100 to 30:70 ethyl acetate/hexane gradient to
afford 6b as a waxy white solid (5.76 g, 96%). Mp: 34–35 ꢀC. 1H NMR
treated with ethylenediamine (201
m
L, 3.00 mmol). After 1 h, the
reaction was heated at 130–135 ꢀC. After 48 h, the reaction was
concentrated in vacuo, treated with satd aq NaHCO3 (5 mL) and
brine (2 mL) and extracted with 1:4 ethanol/dichloromethane
(3ꢁ10 mL). The combined extracts were dried (MgSO4) and con-
centrated in vacuo. Purification by silica gel chromatography elut-
ing with a 100:0 to 20:80 ethyl acetate/1:9 concd NH4OH in ethanol
gradient afforded the free amine as a slightly yellow oil, partly
solidifying after reconcentration from ethanol/water and vacuum
drying (171 mg). The material was dissolved in acetonitrile (5 mL),
treated with 2 M aqueous HCl (0.60 mL), and concentrated in vacuo
to give 4 hydrochloride as an off-white solid (195 mg, 71% from 7).
Mp: 297–299 ꢀC (dec, darkens prior to melting). 1H NMR (DMSO-d6,
(CDCl3, 400 MHz): d 7.89 (1H, app dt, J 1.8, 7.4 Hz), 7.65 (1H, m), 7.33
(1H, app dt, J 0.9, 7.7 Hz), 7.24 (1H, app dt, J 0.9, 8.4 Hz), 5.78 (1H,
m), 5.32 (1H, dd, J 0.7, 10.1 Hz), 5.26 (1H, dd, J 1.1, 17.0 Hz), 4.03 (2H,
d, J 7.4 Hz); 13C NMR (CDCl3):
d
159.5 (d, J 254 Hz), 136.2 (d, J 8 Hz),
131.0, 126.2 (d, J 14 Hz), 124.9, 124.7 (d, J 4 Hz), 124.2, 117.0 (d, J
21 Hz), 60.2 (d, J 3 Hz) ppm; 19F{1H} NMR (CDCl3):
d
ꢂ108.86 ppm;
MS (ESþ): 201.0 (MþH); HRMS: calcd for C9H9FO2SþNaþ, 223.0200;
found (ESI, [MþNa]þ), 223.0195. HPLC purity¼100%.
400 MHz): d 9.26 (2H, br s), 7.66 (1H, dd, J 1.6, 7.9 Hz), 7.52 (1H, app
4.2.3. (E)-1-Chloro-2-(3-chloroprop-1-enylsulfonyl)benzene (7). A
stirred mixture of PdCl2 (0.049 g, 0.030 mmol), CuCl2 (7.37 g,
54.8 mmol), andNaCl(6.94 g,119 mmol) inglacialaceticacid (40 mL)
was heated at 80 ꢀC for 1 h, then treated with 6a (1.98 g, 9.14 mmol)
and heating continued for 48 h. The dark reactionwas cooled, poured
into water (100 mL), and extracted with dichloromethane (100 mL).
The dried (MgSO4) extract was concentrated in vacuo to an oil, which
was chromatographed (silica gel, 40:60 ethyl acetate/hexanes) to
afford a 60:40 mixture of 6a and 7 as a colorless oil (1.95 g). Repeated
chromatographygave some clean7 (0.67 g, 29%) alongwith mixed 6a
dt, J 1.6, 7.2 Hz), 7.26 (1H, d, J 8.7 Hz), 6.97 (1H, app t, J 7.5 Hz), 4.27
(1H, d, J 13.5 Hz), 4.09 (1H, app tt, J 3.0, 11.2 Hz), 3.83 (1H, dd, J 3.3,
14.1 Hz), 3.56 (1H, dd, J 11.3, 14.1 Hz), 3.43–3.44 (2H), 3.23 (1H, app
dt, J 2.5, 13.1 Hz), 3.06 (2H, app t, J 12.0 Hz); MS (ESþ): 239.1
[MþH]þ; HRMS: calcd for C11H14N2O2SþHþ, 239.0849; found (ESI,
[MþH]þ), 239.0854. HPLC purity¼99.9%.
Another sample of free amine 4 was treated with an excess of
trifluoroacetic acid and concentrated in vacuo, then reconcentrated
from acetonitrile and triturated to afford an off-white solid. Mp:
228–229 ꢀC (dec, gas evolution). HPLC purity¼99.1%. The 1H NMR
(400 MHz) spectrum was essentially identical to that reported in
the literature.2d
and 7. 1H NMR (CDCl3, 400 MHz):
d 8.17 (1H, dd, J 1.6, 7.8 Hz), 7.60–
7.53 (2H), 7.48 (1H, app dt, J 1.7, 7.2 Hz), 7.17 (1H, app dt, J 5.2,14.7 Hz),
6.88(1H, dt, J1.7,14.7 Hz), 4.26(2H, dd, J1.7, 5.2 Hz);13CNMR(CDCl3):
d
142.8, 137.3, 134.9, 132.9, 132.0, 131.5, 131.0, 127.5, 41.4 ppm; MS
4.2.7. 1,2,3,4,4a,5-Hexahydro-pyrazino[2,1-c][1,4]benzothiazine-6,6-
dioxide (4). A stirred solution of 8a (376 mg, 1.00 mmol) in 2-
ethoxyethanol (10 mL) under nitrogen was treated with ethyl-
(ESꢂ): 249.0 [MꢂH]ꢂ; HRMS: calcd for C9H8Cl2O2SꢂHꢂ, 248.9549;
found (ESI, [MꢂH]ꢂ), 248.9522. HPLC purity¼97.2%.
enediamine (267 mL, 4.00 mmol) at rt. After 1 h, the reaction was
4.2.4. 1-Chloro-2-[(2,3-dibromopropyl)sulfonyl]benzene
(8a). To
heated to reflux (135 ꢀC) and maintained at reflux for 48 h. The
reaction was cooled and treated with satd aq NaHCO3 (5 mL) and
half-saturated brine (5 mL) and then extracted with 1:4 ethanol/
dichloromethane (3ꢁ15 mL). The dried (MgSO4) extracts were
concentrated in vacuo and purified by silica gel chromatography
eluting with a 100:0 to 20:80 ethyl acetate/1:9 concd NH4OH in
ethanol gradient to afford a partially solidified yellow oil (180 mg
after vacuum drying). This residue was dissolved in acetonitrile (ca.
5 mL) and treated with 2 M aqueous HCl (0.6 mL). The mixture was
concentrated in vacuo and dried under vacuum to give 4 hydro-
chloride as a pale yellow solid (207 mg, 75%). Mp: 297–299 ꢀC (dec,
darkens prior to melting). This sample had essentially identical MS
and 1H NMR spectra compared to the previous hydrochloride ex-
ample. HRMS: calcd for C11H14N2O2SþHþ, 239.0849; found (ESI,
[MþH]þ), 239.0852. HPLC purity¼99.7%.
a stirred solution of 6a (5.23 g, 24.1 mmol) in dichloromethane
(30 mL) at rt was added drop wise a solution of bromine (4.25 g,
26.6 mmol) in dichloromethane (30 mL) over 10 min. After 4 h, the
reaction was concentrated in vacuo to a viscous oil, which solidi-
fied. Compound 8a was isolated as a slightly orange solid (9.03 g,
99%) and used without further purification. Mp: 79–81 ꢀC. 1H NMR
(CDCl3, 400 MHz):
d 8.15 (1H, app dt, J 1.9, 7.9 Hz), 7.65–7.58 (2H),
7.51 (1H, app t, J 7.4 Hz), 4.57 (1H, m), 4.26 (1H, dd, J 5.3, 14.9 Hz),
4.01 (1H, app t, J 7.5 Hz), 3.95 (1H, m), 3.74 (1H, dd, J 7.5, 11.0 Hz)
ppm; 13C NMR (CDCl3):
d 136.6, 135.4, 133.0, 132.1, 131.8, 127.6, 59.4,
40.7, 36.0 ppm; MS (ESIþ): 391.9 [MþNH4]þ; HRMS: calcd for
[C9H9Br2ClO2SþNH4]þ, 391.8717; found (ESI, [MþNH4]þ), 391.8737.
HPLC purity¼100%.
4.2.5. 1-(2,3-Dibromopropylsulfonyl)-2-fluorobenzene
(8b). To
a stirred solution of 6b (5.25 g, 26.2 mmol) in dichloromethane
(25 mL) at rt was added drop wise a solution of bromine (1.49 mL,
28.8 mmol) in dichloromethane (25 mL) over about 5 min. After
3 h, the reaction was concentrated in vacuo to a viscous oil, which
mostly solidified. The product mass was broken up and triturated
with hexanes, then placed under vacuum. Compound 8b was iso-
lated as a very pale orange solid (9.43 g, 100%) and used without
further purification. Mp: 53–55 ꢀC. 1H NMR (CDCl3, 400 MHz):
4.2.8. 1,2,3,4,4a,5-Hexahydro-pyrazino[2,1-c][1,4]benzothiazine-6,6-
dioxide (4). A stirred solution of 8b (1.08 g, 3.00 mmol) in
2-ethoxyethanol (30 mL) at rt under nitrogen was treated with
ethylenediamine (0.80 mL, 12.0 mmol). After 1 h, the reaction was
heated to 130 ꢀC for 23 h, then cooled and concentrated in vacuo.
The residue was treated with satd aq NaHCO3 (10 mL) and water
(5 mL) and then extracted with 1:4 ethanol/dichloromethane
(3ꢁ20 mL). The combined extracts were dried (MgSO4) and con-
centrated in vacuo. Chromatography on silica gel eluting with
a gradient of 0:100 to 25:75 10% concd NH4OH in ethanol/ethyl
acetate gave the free amine as an oil, partly solidifying (ca. 543 mg),
which was dissolved in ethanol (or acetonitrile) and treated with
2 M aqueous HCl (1.15 mL) causing precipitation. Concentration in
vacuo and reconcentration from water followed by trituration with
acetonitrile and suction filtration gave 4 hydrochloride as an off-
white solid (496 mg, 60%) and a second crop (63 mg, 8%) as
a slightly orange solid. Mp: 297–299 ꢀC (dec, darkens prior to
d
7.97 (1H, app dt, J 1.8, 7.4 Hz), 7.70 (1H, m), 7.38 (1H, app dt, J 0.9,
7.8 Hz), 7.28 (1H, app dt, J 0.8, 8.4 Hz), 4.55 (1H, m), 4.17 (1H, dd, J
5.3, 15.2 Hz), 3.94 (1H, dd, J 4.3, 11.1 Hz), 3.85 (1H, dd, J 7.3, 15.2 Hz),
3.74 (1H, dd, J 7.5, 11.1 Hz); 13C NMR (CDCl3):
d 159.7 (d, J 255), 136.9
(d, J 4 Hz), 130.6, 127.1 (d, J 15 Hz), 125.0 (d, J 4 Hz), 117.4 (d, J 20 Hz),
60.7, 40.6, 35.9 ppm; 19F{1H} NMR (CDCl3):
d
ꢂ108.27 ppm; MS (EI):
358.9 [M]þ; HPLC purity¼96.4%.
4.2.6. 1,2,3,4,4a,5-Hexahydro-pyrazino[2,1-c][1,4]benzothiazine-6,6-
dioxide (4). Compound 7 (251 mg, 1.00 mmol) was dissolved in
2-ethoxyethanol (10 mL) at rt under nitrogen. The reaction was
melting). 1H NMR (DMSO-d6, 600 MHz):
dd, J 1.7, 7.8 Hz), 7.52 (1H, ddd, J 1.8, 7.2, 8.8 Hz), 7.26 (1H, d, J
d 9.90 (2H, br s), 7.66 (1H,

2276
R.C. Bernotas, R.J. Dooley / Tetrahedron 66 (2010) 2273–2276
data for the trifluoroacetic acid salt, see, Kikuchi, C.; Ando, T.; Fuji, K.; Okuno, M.;
Morita, E.; Imai, M.; Ushiroda, O.; Koyama, M.; Hiranuma, T. U.S. Patent
6,498,251, 2002; Chem. Abs. 131:87906. Synthesis Example 11b.
8.7 Hz), 6.97 (1H, t, J 7.4 Hz), 4.27 (1H, d, J 13.6 Hz), 4.13 (1H, app tt, J
3.0,11.3 Hz), 3.84 (1H, dd, J 3.3,14.1 Hz), 3.57 (1H, dd, J 11.3,14.3 Hz),
3.50–3.41 (2H), 3.27 (1H, app dt, J 2.7, 13.1 Hz), 3.10–3.01 (2H); 13C
3. Giovannini, R.; Petrini, M. Synlett 1998, 90.
4. All new compounds gave satisfactory spectral data (1H NMR, MS, HRMS) and
were >95% pure by analytical HPLC except 8b for which a high-resolution mass
spectrum could not be obtained.
NMR (DMSO-d6, 151 MHz):
d 145.0, 134.8, 125.4, 124.1, 119.2, 116.6,
52.3, 49.5, 45.8, 44.4, 42.9 ppm; 15N NMR (DMSO-d6, 61 MHz, in-
directly detected by 1H-15N HMBC):
d 73.1, 39.5 ppm (liq. NH3
5. Antane, S.; Bernotas, R. C.; Li, Y.; McDevitt, R.; Yan, Y. Synth. Commun. 2004, 34,
2443 see also; Crandall, J. K.; Pradat, C. J. Org. Chem. 1985, 50, 1327.
6. Ogura, K.; Shibuya, N.; Iida, H. Tetrahedron Lett. 1981, 22, 1519.
7. Najera, C.; Perez-Pinar, A.; Sansano, J. M. Tetrahedron 1991, 47, 6337.
8. The reaction of aryl 2,3-dibromopropylsulfones with 2-thiouracils to
prepare thiazolopyrimidines has been reported Shklyarenko, A. A.;
Chernitsa, B. V.; Yakovlev, V. V. Russ. J. Org. Chem. 2005, 41, 1097.
d
¼0 ppm); MS (ESþ): 239.1 [MþH]þ; HRMS: calcd for
C11H14N2O2SþHþ, 239.0849; found (ESI, [MþH]þ), 239.0847. HPLC
purity¼100%.
References and notes
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Lipson, S.; Sukoff, S.; Zhang, Y. Bioorg. Med. Chem. Lett. 2000, 10, 1991; (c) Kumar,
N.; Jain, P. C.; Anand, N. Indian J. Chem., Sect. B 1979, 17B, 244; (d) For proton NMR
9. Full NMR assignment included 1H NMR, 13C NMR, selective 1H–1H NOESY1D and
homonuclear decoupling experiments, as well as 1H–13C HSQC, 1H–13C 1,1-AD-
.
EQUATE, 1H–13C HMBC, and 1H–15N HMBC.