Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one NS2028

Article abstract of DOI:10.1016/j.tet.2011.05.071

Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 1a are synthesized. Treating 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one oxime (6) with 1,1′-thiocarbonyldiimidazole (1.1 equiv) gave the carbamothioate 8-bromo-4H-[1,2,4]oxadiazolo[3,4

Full text of DOI:10.1016/j.tet.2011.05.071

Tetrahedron 67 (2011) 5437e5443
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Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor
8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one NS2028
*
Andrey A. Berezin, Panayiotis A. Koutentis , Manolis J. Manos
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus
a r t i c l e i n f o
a b s t r a c t
Article history:
Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 1a are synthesized. Treating
8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one oxime (6) with 1,10-thiocarbonyldiimidazole (1.1 equiv)
gave the carbamothioate 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) in 83%
yield. Alternatively reacting NS2028 1a with P2S5 (0.5 equiv) affords the carbamothioate 3a in 80% yield.
Similar treatment of 8-aryl substituted NS2028 analogues 1bed with P2S5 gave the carbamothioates
3bed in 64e91% yields. Although quite stable, the carbamothioates 3aed could be thermally iso-
merized in the presence of Cu (10 mol %) to afford the thiocarbamates 4aed in high yields. Interestingly,
in the case of carbamothioate 3a Pd and In metals also facilitated the isomerization. Furthermore,
treatment of the thiocarbamates 4aed with P2S5 (0.5 equiv) affords the carbamodithioates 5aed in
72e89% yields. All new compounds are fully characterized including single crystal X-ray data for car-
bamothioate 3a and thiocarbamate 4a. Finally, a mechanism is proposed for the carbamothioate to
thiocarbamate isomerization.
Received 14 March 2011
Received in revised form 6 May 2011
Accepted 16 May 2011
Available online 25 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Soluble guanylate cyclase (sGC) is the only known physiological
receptor for nitric oxide (NO). On binding to NO the activity of sGC
increases 400-fold, promoting the conversion of guanosine 50-tri-
phospate (GTP) to the second messenger guanosine 30,50-cyclic
monophosphate (cGMP) and pyrophosphate. cGMP acts to regulate
various effector proteins, including protein kinases, phosphodies-
terases and ion channels.1 As such inhibitors of sGC can be used to
regulate NO related signalling processes and to lower cGMP
activity.2
8-Bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]-benzoxazin-1-one
(NS2028) 1a is a specific inhibitor of soluble guanylate cyclase
(sGC). Recent applications of NS2028 1a include the development
of inhibitors for lymphangiogenesis that can help prevent the
metastasis of solid tumours,3 for the treatment of dermatological
diseases and in cosmetic skin care.3,4 Furthermore, NS2028 has
been used for neural thermoprotection against heat stroke or hy-
perthermia via inhibition of the PKG pathway,5 and for the pre-
vention and treatment of dental disorders.6
Despite being known for approximately 15 years, the synthesis
of NS2028 1a was only fully reported recently.7 Not surprisingly,
only a few analogues have been prepared and as such the phar-
macophore structure of this compound remains unclear. Never-
theless, replacing the 8-bromo substituent by 4-methoxyphenyl or
by 3-trifluoromethylphenyl gave analogues with interesting bi-
ological profiles, while replacing the 1,2,4-oxadiazolone ring with
1,2,4-triazolone to give 8-bromo-2,4-dihydro-1H-benzo[b][1,2,4]
triazolo[4,3-d][1,4]oxazin-1-one 2 led to a large decrease in activity
demonstrating the importance of the former.7a Carbamides are far
less electrophilic than carbamates and this indicated that in-
troducing further structural modifications of the oxadiazole were
warranted. The preparation of NS2028 analogues sporting carba-
mothioate 3, thiocarbamate 4 and carbamodithioate 5 moieties
would therefore be of interest.
We recently developed a non product specific synthesis of C-8
substituted analogues using SuzukieMiyaura coupling reactions
and NS2028 as a building block.7b Now we wish to report our
* Corresponding author. Tel.: þ357 22 892783; fax: þ357 22 892809; e-mail
address: koutenti@ucy.ac.cy (P.A. Koutentis).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.071

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A.A. Berezin et al. / Tetrahedron 67 (2011) 5437e5443
efforts to synthesize a library of 1,2,4-oxadiazole-5(4H)-thione
(carbamothioate), 1,2,4-thiadiazol-5(4H)-one (thiocarbamate) and
1,2,4-thiadiazole-5(4H)-thione (carbamodithioate) analogues 3e5
of NS2028 that incorporate structural modifications at C-8.
2.2. Isomerization of NS2028 carbamothioates 3 to NS2028
thiocarbamates 4
Interestingly, prolonged heating (5 h) of the 6-bromo-2H-benzo
[b][1,4]oxazin-3(4H)-one oxime (6) and 1,10-thiocarbonyldiimidazole
(TCDI) reaction mixture (Scheme 1) led to the formation of a side
product that co-ran with the NS2028 1a on TLC. The product was
isolated as pale yellow needles (mp 157e158 ꢀC) and electron impact
mass spectrometry gave a parent ion m/z (EI) 284 Da (98%) with an
isotope pattern typical of one bromine atom. Elemental combustion
analysis supported the formula C9H5BrN2O2S, which was isomeric
with the carbamothioate 3a. IR spectroscopy indicated the presence
2. Results and discussion
2.1. Preparation of NS2028 thione
NS2028 1a can be prepared from 6-bromo-2H-benzo[b][1,4]
oxazin-3(4H)-one oxime (6) on treatment with 1,10-carbon-
yldiimidazole (CDI) in 95% yield.7a Similar treatment of the oxime 6
with 1,10-thiocarbonyldiimidazole (TCDI) (1.1 equiv) in dry THF at
ca. 66 ꢀC for 0.5 h gave the carbamothioate 8-bromo-4H-[1,2,4]
oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) in 83% yield
(Scheme 1).
of a carbonyl stretch at n
(C]O) 1647 cmꢁ1, that was not present in the
carbamothioate 3a, while 1H and 13C NMR spectroscopy suggested
the substitution pattern on the arene remained essentially the same,
with only a noticeable change was observed in the most down field
signals. As such we postulated that the new product was the isomeric
thiocarbamate 8-bromobenzo[b][1,2,4]thiadiazolo-[4,3-d][1,4]-oxa-
zin-1(4H)-one (4a).
The structure of the thiocarbamate 4a was also confirmed by
single crystal X-ray crystallography, thus providing supporting
structure assignments for both carbamothioates and thio-
carbamates (Fig. 2). A close comparison of the spectroscopic data
revealed useful handles for identifying between the two isomers.
The thione carbon resonance in the 13C NMR spectra of the carba-
mothioates 3aed fell in a narrow range dC]S 179.2e181.0 ppm,
while that of the carbonyl of the thiocarbamates 4aed fell in the
narrow range dC]O 174.3e174.9 ppm. Similarly, the H-9 resonance
in the 1H NMR spectra was distinctly different for both sets of
compounds with the thione functionality deshielding the H-9 hy-
drogen greater than the carbonyl, dH-9 9.32e9.51 ppm (carbamo-
thioates 3aed) versus dH-9 8.53e8.73 ppm (thiocarbamates 4aed).
Scheme 1.
Alternatively, NS2028 1a can be reacted with diphosphorus
pentasulfide (0.5 equiv) in refluxing xylene for 48 h to give the
carbamothioate 3a in 80% yield. The thionation worked equally well
for 8-aryl substituted analogues bearing both electron withdrawing
and donating substituents 1b (R¼4-MeOC6H4), 1c (R¼4-ClC6H4)
and 1d (R¼3-O2NC6H4) (Scheme 2).
Scheme 2.
The carbamothioate analogues of NS2028 3aed were suffi-
ciently stable to be recrystallized from CHCl3 enabling full charac-
terization, including elemental analysis and 13C NMR spectroscopy.
Since 1,2,4-oxadiazole-5(H)-thiones are known to thermally
isomerize to give 1,2,4-thiadiazol-5(H)-ones,8aef we also solved
a single crystal X-ray structure for compound 3a, to fully support
the structural assignment (Fig. 1).
Fig. 2. Ball and stick representation of the crystal structure of 8-bromo-4H-[1,2,4]
thiadiazolo-[3,4-c][1,4]benzoxazin-1-one (4a) with crystallographic atom labelling.
Hydrogen atoms are omitted for clarity.
More surprisingly, isomerization was also observed when carba-
mothioate 3a was subjected to SuzukieMiyaura coupling conditions.
As such, treating carbamothioate 3a with 4-methoxyphenylboronic
€
acid (1.5 equiv), Pd(OAc)2 (5 mol %) and Hunig’s base (3 equiv) in di-
oxane/H2O (4:1) at ca. 110 ꢀC for 2.5 h gave not the expected C-8
arylated analogue 3b but the thiocarbamate 4a in a moderate 54%
yield together with recovered carbamothioate 3a (28%) (Scheme 3).
Fig. 1. Ball and stick representation of the crystal structure of 8-bromo-4H-[1,2,4]-
oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) with crystallographic atom labelling.
Hydrogen atoms are omitted for clarity.
Scheme 3. Reagentand conditions: (i) 4-MeOC6H4B(OH)2 (1.5 equiv), Pd(OAc)2 (5 mol %),
i-Pr2NEt (3 equiv), dioxane/H2O (4:1), 110 ꢀC, 2.5 h.

A.A. Berezin et al. / Tetrahedron 67 (2011) 5437e5443
5439
The isomerization of carbamothioates into thiocarbamates is
known to proceed either photochemically, or thermally and in the
latter cases copper was found to be an effective catalyst.8 In light of
this, we isomerized a pure sample of carbamothioate 3a by heating
a toluene solution of the carbamothioate with Cu powder (10 mol
%) at ca. 110 ꢀC for 1 h (Table 1). The isomerization also occurred
when the Cu catalyst was replaced by Pd(OAc)2, which partly
explained the failure of the SuzukieMiyaura reaction of the car-
bamothioate 3a. In fact, the use of either heterogeneous or homo-
geneous Pd(0) sources, Pd/C (5 mol %) or Pd(OAc)2 (5 mol %),
respectively, also led to isomerization but the palladium catalyzed
reactions were less clean than those using catalytic Cu powder. 1H
NMR spectroscopy of the products mixtures from the Pd(OAc)2
catalyzed isomerization tentatively identified one of the contami-
nates to be NS2028 1a. Fortunately recrystallization of these mix-
tures gave pure thiocarbamate 4a. Switching to In powder (1 equiv)
in dioxane at reflux led to a clean and quantitative isomerization
but the reaction failed when either catalytic In (10 mol %) was used
or when dioxane was replaced by toluene. Owing to the relative
costs of In, Pd and Cu we carried out all subsequent isomerizations
of carbamothioates 3bed using catalytic Cu powder (Table 1).
7, which then undergoes a ring open-ring closure sequence via
intermediates 8 and 9 to give the more stable thioester 4a
(Scheme 4).
Scheme 4.
Tentatively, the Pd(OAc)2 promoted isomerization may be
catalyzed by the presence of Pd(0) species generated in the reaction
mixture. This was supported by the successful isomerization in the
presence of heterogeneous and homogenous sources of Pd(0), Pd/C
and the Pd2(dba)2, respectively. Interestingly, the latter homoge-
neous catalyst gave a very rapid reaction (20 min) (Table 1).
Furthermore, it was of interest that indium powder (1 equiv) gave
the cleanest reactions but that these were also dependent on the
solvent used, working well with dioxane but not with toluene,
which could be of mechanistic interest since a purely radical
mechanism should not be affected so significantly by solvent
polarity.
Table 1
Metal catalyzed isomerization of the carbamothioates 3 into the thiocarbamates 4
2.4. Preparation of carbamodithioates 5 via thionation of
thiocarbamates 4
R
Catalyst (mol %) Solvent (mL) Temp (ꢀC) Time (h) Yielda (%)
Br
Br
Br
Br
Br
Br
Br
Cu (10)
Pd2(OAc)2 (10) PhMe (0.5)
Pd2(dba)2 (10)
Pd/C (20)
In (100)
PhMe (0.5)
110
110
110
110
1
2
0.3
3
1
24
24
1
4a (88)
4a (93)
4a (90)
4a (81)
Finally, treatment of the thiocarbamates 4aed with diphos-
phorus pentasulfide (0.5 equiv) in xylene at ca. 150 ꢀC for 12 h gave
the carbamodithioates 5aed in good yields (72e89%) (Scheme 5).
PhMe (0.5)
PhMe (0.5)
Dioxane (0.5) 100
Dioxane (0.5) 100
PhMe (0.5)
PhMe (0.5)
PhMe (0.5)
PhMe (0.5)
4a (93)
b
In (10)
In (100)
b
110
110
110
110
4-MeOC6H4 Cu (10)
4-ClC6H4 Cu (10)
3-O2NC6H4 Cu (20)
4b (86)
4c (88)
4d (80)
1
1
a
Recrystallized yields.
Incomplete reaction.
b
All three 8-aryl substituted carbamothioates 3bed isomerized
in the presence of Cu(0) in good yields (80e88%), however, we
found that the 3-nitrophenyl analogue isomerized more slowly
using only 10 mol % of copper and for the reaction to reach com-
pletion in 1 h 20 mol % of copper powder was needed. Furthermore,
treating a pure sample of the thiocarbamate 4a with indium, cop-
per or palladium led only to recovery of unreacted thiocarbamate.
Despite this stability, when the SuzukieMiyaura coupling chemis-
try was attempted with the 8-bromo derivative 4a to prepare in-
dependently the thiocarbamates 4bed we failed to get any
reaction. This is now under investigation.
Scheme 5.
Similar to the carbamothioates 3aed the carbamodithioates
5aed gave a down field signal for H-9 in the 1H NMR spectra dH-9
9.71e9.86 ppm owing to the deshielding effect of the thione, while
the thiocarbonyl group gave the most down field signals in the 13C
NMR spectra, dC]S 194.6e195.2 ppm. As with the thiocarbamate 4a
attempted SuzukieMiyaura coupling reactions with the carbamo-
dithioate 5a only gave back unreacted starting material. With these
final compounds prepared we now had a small library of NS2028
analogues with a systematic variation of substituent at C-8 com-
bined with a variation of the oxadiazolone moiety. Biological
studies on these new analogues of the NS2028 sGC inhibitor are
now underway.
2.3. Mechanistic rational for isomerization of
carbamothioates 3 into thiocarbamates 4
To the best of our knowledge the isomerization of 1,2,5-
thiadiazole-5(H)-thiones into 1,2,5-thiadiazol-5(H)-ones using
either indium or palladium reagents has not been reported. The
mechanism for the indium and palladium metal promoted isom-
erization, however, could be similar to that proposed by Pelter and
3. Conclusion
NS2028 thione 3a has been prepared via thionation of NS2028
1a using P2S5 and via the reaction of 6-bromo-2H-benzo[b][1,4]
Sumengen,8a i.e., single electron transfer to give the radical anion
€

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A.A. Berezin et al. / Tetrahedron 67 (2011) 5437e5443
oxazin-3(4H)-one oxime (6) with TCDI in 80 and 83% yields,
respectively. Several 8-aryl analogues of NS2028 1bed were also
readily thionated to give the corresponding thiones 3bed in high
yields. Treating the carbamothioate 3a with either In, Cu or Pd led
to isomerization and provided the thiocarbamate 4a in good yields.
Cu and Pd could be used catalytically; however, the reactions were
accompanied by minor side products. On the other hand the
reactions with 1 equiv of indium powder gave only pure product.
Treatment of the thiocarbamates 4aed with P2S5 gave the corre-
sponding carbamodithioates 5aed in good yields. The scope of
using these reagents for similar isomerizations is now being
investigated. Finally, the biological properties of these new NS2028
analogues are currently under investigation.
onset: 184 ꢀC, peak max: 190 ꢀC (from chloroform), Rf (DCM) 0.72;
found: C, 37.9; H, 1.7; N, 9.8. C9H5BrN2O2S requires C, 37.9; H, 1.8; N,
9.8%; lmax (DCM)/nm 230 (log 3 2.93), 232 inf (2.91), 240 inf (2.83),
273 inf (3.02), 279 (3.15), 298 inf (3.10), 303 (3.11); nmax/cmꢁ1
3102w, 3075w and 3015w (Ar CH), 2913w, 1771w, 1626m, 1595w,
1487s, 1449m, 1387m, 1360s, 1296m, 1260m, 1242m, 1219w, 1136w,
1115m, 1074w, 1042w, 1030m, 993w, 949w, 941w, 918w, 887w,
870m, 854w, 831m, 816m, 785m; dH (300 MHz, CDCl3) 9.32 (1H, d,
J 2.1, H-9), 7.45 (1H, dd, J 8.7, 2.3, H-7), 7.06 (1H, d, J 8.7, H-6), 5.19
(2H, s, CH2O); dC (75 MHz, DMSO-d6) 179.2 (C]S), 152.5 (Cq), 144.8
(Cq), 131.5 (Ar CH), 132.4 (Cq), 119.9 (Ar CH), 118.7 (Ar CH), 113.4 (Cq),
59.5 (CH2O); m/z (EI) 286 (Mþþ2, 100%), 284 (Mþ, 97), 258 (6), 256
(6), 226 (24), 224 (22), 212 (10), 199 (38), 197 (37), 186 (7), 184 (8),
172 (52), 170 (66), 158 (15), 156 (18), 144 (6), 129 (5), 117 (12), 109
(8), 103 (6), 90 (18), 76 (77), 63 (95), 50 (44).
4. Experimental
4.1. General methods and materials
4.2.2. 8-Bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-
thione (3a), method B (typical procedure, see Scheme 2). To a solution
of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one (1a)
(100 mg, 0.372 mmol) in xylene (5 mL) was added P2S5 (41.3 mg,
0.186 mmol). The reaction mixture was then allowed to stir at ca.
140 ꢀC for 48 h and then cooled to ca. 20 ꢀC. The solvent was re-
moved in vacuo and the residue dissolved in DCM (5 mL), adsorbed
onto silica and chromatographed (DCM) to give the title compound
3a (86 mg, 80%) as colourless prisms, mp (DSC) onset: 184 ꢀC, peak
max: 190 ꢀC (from chloroform), Rf (DCM) 0.72; identical to that
described above.
Toluene and xylene (mixture of isomers) were freshly distilled
from sodium under argon. Reactions were protected from atmo-
spheric moisture by CaCl2 drying tubes. All volatiles were removed
under reduced pressure. All reaction mixtures and column eluents
were monitored by TLC using commercial glass backed thin layer
chromatography (TLC) plates (Merck Kieselgel 60 F254). The plates
were observed under UV light at 254 and 365 nm. The technique of
dry flash chromatography was used throughout for all non-TLC scale
chromatographic separations using Merck Silica Gel 60 (less than
0.063 mm).9 Melting and decomposition points were determined
using a TA Instruments DSC Q1000 with samples hermetically
sealed in aluminium pans under an argon atmosphere; using
heating rates of 5 ꢀC/min. Solvents used for recrystallization are
indicated after the melting point. UV spectra were obtained using
a PerkineElmer Lambda-25 UV/vis spectrophotometer and in-
flections are identified by the abbreviation ‘inf’. IR spectra were
recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer with
a Pike Miracle Ge ATR accessory and strong, medium and weak
peaks are represented by s, m and w, respectively. 1H NMR spectra
were recorded on a BrukerAvance 300 machine at 300 MHz. 13C
NMR spectra were recorded on a BrukerAvance 300 or Bruker-
Avance 500 machines (at 75 and 125 MHz, respectively). Deuterated
solvents were used for homonuclear lock and the signals are refer-
enced to the deuterated solvent peaks. Low resolution (EI) mass
spectrawere recorded on a Shimadzu Q2010 GC/MS with direct inlet
probe. 8-Bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
(NS2028) 1a,7b 8-(4-methoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c]
[1,4]benzoxazine-1-one 1b,7b 8-(4-chlorophenyl)-4H-[1,2,4]oxa-
diazolo[3,4-c][1,4]benzoxazine-1-one 1c7b and 8-(3-nitrophenyl)-
4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-one 1d7b were prepared
using literature procedures. Copper fine powder GR particle size
4.2.3. 8-(4-Methoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azine-1-thione (3b), method B. Similar treatment of 8-(4-
methoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
1b (100 mg, 0.338 mmol) with P2S5 (41.3 mg, 0.186 mmol) in xylene
(5 mL) at ca. 140 ꢀC for 48 h gave the title compound 3b (90 mg, 86%)
as colourless cotton needles, mp (DSC) onset: 201.6 ꢀC, peak max:
201.8 ꢀC (from 1,2-dichloroethane), Rf (DCM) 0.56; found: C, 61.4;
H, 3.8; N, 8.9. C16H12N2O3S requires C, 61.5; H, 3.9; N, 9.0%; lmax
(DCM)/nm 228 (log
3
3.08), 277 (3.50); nmax/cmꢁ1 3015w (Ar CH),
2963w, 2945w, 2918w, 2841w,1630w,1609m,1528w,1499s,1487w,
1470w, 1458w, 1437w, 1418w, 1389w, 1354s, 1319m, 1294m, 1277m,
1254m, 1238s, 1219m, 1186m, 1105s, 1051w, 1040m, 1032m, 1020m,
878w, 841m, 833m, 818m, 810m, 802m, 779w; dH (300 MHz, CDCl3)
9.37 (1H, d, J 2.3, H-9), 7.55 (2H, d, J 8.9, Ar H), 7.50 (1H, dd, J 8.5, 2.3,
H-7), 7.20 (1H, d, J 8.5, H-6), 7.01 (2H, d, J 8.9, Ar H), 5.20 (2H, s,
CH2O), 3.86 (3H, s, CH3O); dC (75 MHz, CDCl3) 179.8 (C]S), 159.6
(Cq), 151.8 (Cq), 144.1 (Cq), 136.7 (Cq), 131.6 (Cq), 128.0 (Ar CH), 126.9
(Ar CH), 122.6 (Cq), 118.2 (Ar CH), 115.3 (Ar CH), 114.5 (Ar CH), 59.8
(CH2O), 55.4 (CH3O); m/z (EI) 312 (Mþ, 100%), 284 (9), 272 (7), 251
(9), 244 (7), 237 (23), 225 (17), 209 (20), 201 (4), 195 (4), 182 (5),
169 (7), 155 (5), 140 (13), 127 (19), 114 (8), 101 (5), 89 (6), 77 (10), 63
(11), 51 (6).
<63 mm was purchased from Merck; phosphorus pentasulfide
(P4S10) 99% from Aldrich.
4.2.4. 8-(4-Chlorophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azine-1-thione (3c), method B. Similar treatment of 8-(4-
chlorophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
1c (100 mg, 0.333 mmol) with P2S5 (41.3 mg, 0.186 mmol) in xylene
(5 mL) at ca. 140 ꢀC for 48 h gave the title compound 3c (95 mg, 91%)
as pink prisms, mp (DSC) onset: 218 ꢀC, peak max: 221 ꢀC (from 1,2-
dichloroethane), Rf (DCM) 0.71; found: C, 56.9; H, 2.8; N, 8.9.
C15H9ClN2O2S requires C, 56.9; H, 2.9; N, 8.8%; lmax (DCM)/nm 228
4.2. Thionation of 8-substituted 4H-[1,2,4]oxadiazolo[3,4-c]
[1,4]benzoxazin-1-ones
4.2.1. 8-Bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-
thione (3a), method A (Scheme 1). To the solution of 6-bromo-2H-
1,4-benzo[b][1,4]oxazin-3(4H)-one oxime (6) (1.00 g, 4.11 mmol) in
dry THF (10 mL) was added thiocarbonyl diimidazole (TCDI)
(0.807 g, 4.53 mmol). The reaction mixture was then allowed to stir
at ca. 66 ꢀC for 0.5 h and then cooled to ca. 20 ꢀC. The solvent was
removed in vacuo and the residue dissolved in DCM (25 mL) and
washed with water (2ꢂ25 mL). The organic layer was dried
(Na2SO4), filtered and the filtrate was evaporated under reduced
pressure. The resulting solid material was recrystallized to give the
title compound 3a (0.97 g, 83%) as colourless prisms, mp (DSC)
(log 3
3.26), 272 (3.52), 301 inf (3.09); nmax/cmꢁ1 3080w, 3003w (Ar
CH), 2913w, 2866w, 1628w, 1609w, 1516w, 1485s, 1454m, 1410m,
1387w, 1358s, 1319w, 1273m, 1246w, 1223w, 1190w, 1146w, 1099s,
1049w, 1038m, 1020w, 1013m, 959w, 885w, 849w, 833m, 820s,
797w; dH (300 MHz, acetone-d6) 9.49 (1H, d, J 2.3, H-9), 7.71 (1H,
dd, J 8.5, 2.3, H-7), 7.70 (2H, d, J 8.7, Ar H), 7.54 (2H, d, J 8.7, Ar H),
7.33 (1H, d, J 8.5, H-6), 5.53 (2H, s, CH2O); dC (75 MHz, acetone-d6)

A.A. Berezin et al. / Tetrahedron 67 (2011) 5437e5443
5441
181.0 (C]S), 153.6 (Cq), 146.4 (Cq), 138.9 (Cq), 135.3 (Cq), 134.2 (Cq),
130.0 (Ar CH), 129.1 (Ar CH), 127.9 (Ar CH), 124.1 (Cq), 119.3 (Ar CH),
115.9 (Ar CH), 60.7 (CH2O); m/z (EI) 318 (Mþþ2, 35%), 316 (Mþ, 100),
290 (5), 288 (14), 258 (15), 256 (32), 242 (13), 229 (13), 216 (6), 202
(18), 200 (10), 177 (6), 164 (8), 153 (17), 139 (48), 126 (14), 113 (7),
101 (9), 87 (7), 75 (15), 69 (8), 63 (13), 51 (8).
(0.5 mL) at ca. 110 ꢀC for 1 h gave the title compound 4b (43 mg,
86%) as colourless cotton needles, mp (DSC) onset: 107 ꢀC, peak
max: 108 ꢀC (from acetone/pentane), Rf (DCM) 0.47; found: C, 61.5;
H, 3.8; N, 8.8. C16H12N2O3S requires C, 61.5; H, 3.9; N, 9.0%; lmax
(DCM)/nm 230 inf (log
3
3.26), 263 (3.48); nmax/cmꢁ1 3011w (Ar
CH), 2970w, 2941w, 2835w, 1713s (C]O), 1703m, 1686m, 1665w,
1612m, 1595m, 1587m, 1555w, 1526w, 1497s, 1447m, 1412m, 1369s,
1314m, 1292m, 1277m, 1260m, 1238s, 1225m, 1188m, 1180m,
1146m, 1065m, 1045s, 1018s, 885w, 878w, 833m, 814s, 804s, 779m,
768w; dH (300 MHz, acetone-d6) 8.62 (1H, d, J 2.1, H-9), 7.58 (2H, d,
J 8.9, Ar H), 7.52 (1H, dd, J 8.5, 2.1, H-7), 7.23 (1H, d, J 8.5, H-6), 7.04
(2H, d, J 8.9, Ar H), 5.11 (2H, s, CH2O), 3.85 (3H, s, CH3O); dC (75 MHz,
acetone-d6) 174.9 (C]O),160.4 (Cq),150.3 (Cq),145.7 (Cq),136.6 (Cq),
132.8 (Cq), 128.6 (Ar CH), 126.2 (Ar CH), 125.8 (Cq), 118.6 (Ar CH),
116.2 (Ar CH), 115.2 (Ar CH), 66.3 (CH2O), 55.6 (OCH3); m/z (EI): 312
(Mþ, 100%), 284 (21), 269 (4), 251 (10), 238 (19), 225 (21), 210 (9),
195 (6), 167 (3), 153 (3), 140 (7), 127 (7), 119 (3), 115 (4), 105 (3), 89
(3), 77 (4), 63 (5), 51 (3).
4.2.5. 8-(3-Nitrophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azine-1-thione (3d), method B. Similar treatment of 8-(3-
nitrophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one (1d)
(150 mg, 0.482 mmol) with P2S5 (41.3 mg, 0.186 mmol) in xylene
(5 mL) at ca. 140 ꢀC for 48 h gave the title compound 3d (67 mg, 64%)
as yellow prisms, mp (DSC) onset: 223 ꢀC, peak max: 226 ꢀC (from
1,2-dichloroethane), Rf (DCM) 0.70; found: C, 54.9; H, 2.7; N, 12.7.
C15H9N3O4S requires C, 55.0; H, 2.8; N, 12.8%; lmax (DCM)/nm 230
(log
3
3.39), 258 (3.58), 272 inf (3.55), 295 inf (3.21); nmax/cmꢁ1
3067w (Ar CH), 1624w, 1607w, 1558w, 1531s, 1510m, 1474m, 1460m,
1441w, 1427w, 1391m, 1371s, 1348s, 1321m, 1310w, 1273m, 1263m,
1238w, 1213w, 1144w, 1111m, 1084w, 1053w, 1042m, 1020m, 982w,
962w, 934w, 914w, 889m, 881m, 839m, 827m, 806s, 760w; dH
(300 MHz, CDCl3) 9.51 (1H, d, J 2.3, H-9), 8.46 (1H, dd, J 1.9, 1.9, H-20),
8.25 (1H, ddd, J 8.2, 2.2, 1.0, Ar H), 7.95 (1H, ddd, J 7.8, 1.8, 1.0, Ar H),
7.67 (1H, dd, J 8.0, 8.0, H-50), 7.61 (1H, dd, J 8.6, 2.2, H-7), 7.31 (1H, d,
J 8.5, H-6), 5.27 (2H, s, CH2O); dC (125 MHz, CDCl3) 179.7 (C]S), 151.5
(Cq), 148.9 (Cq), 145.5 (Cq), 140.8 (Cq), 134.4 (Cq), 132.9 (Ar CH), 130.2
(Ar CH),127.6 (Ar CH),123.0 (Cq),122.7 (Ar CH),121.7 (Ar CH),118.8 (Ar
CH),116.0 (Ar CH), 59.8 (CH2); m/z (EI): 327 (Mþ,100%), 299 (25), 267
(32), 253 (13), 241 (15), 221 (9), 213 (5), 209 (9), 207 (7),193 (28),179
(5), 167 (43), 153 (18), 139 (75), 126 (21), 113 (9), 100 (5), 89 (9), 76
(12), 70 (7), 63 (19), 60 (8), 50 (9).
4.3.3. 8-(4-Chlorophenyl)-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzox-
azine-1-one (4c). Similar treatment of 8-(4-chlorophenyl)-4H-
[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-thione (3c) (50.0 mg,
0.158 mmol) with copper powder (1.02 mg, 0.016 mmol) in toluene
(0.5 mL) at ca.110 ꢀC for 1 h gave the title compound 4c (44 mg, 88%)
as colourless cotton needles, mp (DSC) onset: 195 ꢀC, peak max:
196 ꢀC (from chloroform), Rf (DCM) 0.47; found: C, 56.9; H, 2.8; N,
8.9. C15H9ClN2O2S requires C, 56.9; H, 2.9; N, 8.8%; lmax (DCM)/nm
230 inf (log
3
3.33), 256 (3.53); nmax/cmꢁ1 3103w, 1695s (C]O),
1670m, 1616w, 1597m, 1551w, 1528w, 1516w, 1485s, 1443m, 1402m,
1366m, 1315w, 1287m, 1267w, 1250m, 1229m, 1194w, 1144m,
1097m, 1069w, 1061m, 1036m, 1013m, 991w, 891w, 885w, 843w,
827w, 814s, 793w, 760m; dH (300 MHz, acetone-d6) 8.67 (1H, d, J
1.9, H-9), 7.66 (2H, d, J 8.5, Ar H), 7.59 (1H, dd, J 8.5, 2.1, H-7), 7.51
(2H, d, J 8.5, Ar H), 7.27 (1H, d, J 8.5, H-6), 5.13 (2H, s, CH2O); dC
(75 MHz, CDCl3) 174.3 (C]O), 148.3 (Cq), 145.2 (Cq), 138.1 (Cq), 135.6
(Cq), 133.8 (Cq), 129.1 (Ar CH), 128.2 (Ar CH), 126.1 (Ar CH), 124.8
(Cq), 118.0 (Ar CH), 116.4 (Ar CH), 65.7 (CH2O); m/z (EI): 318 (Mþþ2,
36%), 316 (Mþ, 100), 290 (16), 288 (41), 261 (6), 255 (16) 242 (25),
230 (15), 214 (9), 200 (4), 177 (15), 164 (5), 152 (22), 144 (7), 139
(33), 126 (14), 113 (6), 99 (6), 89 (6), 75 (14), 69 (5), 63 (10), 51 (7).
4.3. Isomerization of 8-substituted 4H-[1,2,4]oxadiazolo[3,4-
c][1,4]benzoxazin-1-thiones
4.3.1. 8-Bromo-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzoxazine-1-one
(4a) (typical procedure, see Table 1). To a solution of 8-bromo-4H-
[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-thione (3a) (49.9 mg,
0.175 mmol) in toluene (0.5 mL) was added copper powder (1.14 mg,
0.018 mmol). The reaction mixture was then allowed to stir at ca.
110 ꢀC for 1 h and then cooled to ca. 20 ꢀC. The solvent was removed
in vacuo and the residue dissolved in DCM (5 mL). This solution was
passed through a thin layer of silica gel and then rinsed with addi-
tional DCM. The filtrate was evaporated in vacuo to give the crude
product with quantitative yield. Recrystallization of the crude
product gave the title compound 4a (44 mg, 88%) as pale yellow
needles, mp (DSC) onset: 157 ꢀC, peak max: 158 ꢀC (from acetone), Rf
(DCM) 0.56; found: C, 38.1; H, 1.9; N, 9.8. C9H5BrN2O2S requires C,
4.3.4. 8-(3-Nitrophenyl)-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzox-
azine-1-one (4d). Similar treatment of 8-(3-nitrophenyl)-4H-[1,2,4]
oxadiazolo[3,4-c][1,4]benzoxazin-1-thione (3d) (50.1 mg, 0.153 mmol)
with copper powder (1.91 mg, 0.030 mmol) in toluene (0.5 mL) at
ca. 110 ꢀC for 1 h gave the title compound 4d (40 mg, 80%) as pale
yellow needles, mp (DSC) onset: 198 ꢀC, peak max: 198 ꢀC (from
chloroform), Rf (DCM) 0.33; found: C, 55.2; H, 2.7; N, 12.9.
C15H9N3O4S requires C, 55.1; H, 2.8; N, 12.8%; lmax (DCM)/nm 232
38.0; H, 1.8; N, 9.8%; lmax (DCM)/nm 232 (log 3 3.28), 255 inf (3.10),
261 inf (3.04), 288 (2.95), 295 inf (2.92); nmax/cmꢁ13113w, 3076w (Ar
CH), 3005w, 2909w, 1879w, 1753w, 1674s (C]O), 1649m, 1612m,
1595m, 1578w, 1555w, 1528w, 1483s, 1447w, 1429m, 1366s, 1290m,
1258m, 1246w, 1215m, 1140m, 1080w, 1057s, 1020s, 997w, 941w,
878m, 826m, 812m, 785m, 777m; dH (300 MHz, acetone-d6) 8.53
(1H, d, J 2.5, H-9), 7.46 (1H, dd, J 8.7, 2.3, H-7), 7.16 (1H, d, J 8.7, H-6),
5.12 (2H, s, CH2O); dC (125 MHz, acetone-d6) 174.9 (C]O),149.7 (Cq),
146.2 (Cq),131.1 (Ar CH),126.7 (Cq),121.1 (Ar CH),120.2 (Ar CH),115.2
(Cq), 66.4 (CH2O); m/z (EI): 286 (Mþþ2,100%), 284 (Mþ, 98), 258 (59),
256 (61), 231 (6), 229 (6), 225 (15), 223 (15), 212 (27), 210 (25), 200
(17), 198 (18), 184 (10), 182 (9), 177 (9), 170 (7), 156 (7), 149 (9), 129
(7), 119 (4), 109 (5), 103 (28), 76 (42), 72 (13), 63 (38), 50 (25).
inf (log 3
3.49), 255 (3.63), 320 (2.37); nmax/cmꢁ1 3094w, 3073w (Ar
CH), 2995w, 1711s (C]O), 1692m, 1647w, 1614w, 1585m, 1535s,
1510s, 1477m, 1449m,1425m,1369m, 1344s,1302w, 1285m,1275m,
1246m, 1225m, 1177w, 1152m, 1103w, 1090w, 1067m, 1057m,
1049m,1030s, 999w, 951w, 935w, 922w, 903w, 876m, 860m, 826m,
800m, 791m, 772m; dH (300 MHz, CDCl3) 8.73 (1H, d, J 2.1, H-9),
8.43 (1H, dd, J 2.0, 2.0, H-20), 8.22 (1H, ddd, J 8.2, 2.2, 1.0, Ar H), 7.91
(1H, ddd, J 7.8, 1.8, 1.0, Ar H), 7.63 (1H, dd, J 7.9, 7.9, H-50), 7.50 (1H,
dd, J 8.5, 2.3, H-7), 7.26 (1H, d, J 8.5, H-6), 5.00 (2H, s, CH2O); dC
(75 MHz, CDCl3) 174.3 (C]O), 148.8 (Cq), 148.0 (Cq), 145.9 (Cq), 141.3
(Cq), 134.2 (Cq), 132.9 (Ar CH), 129.9 (Ar CH), 126.4 (Ar CH), 125.0
(Cq), 122.3 (Ar CH), 121.8 (Ar CH), 118.3 (Ar CH), 116.6 (Ar CH), 65.7
(CH2O); m/z (EI): 327 (Mþ, 100%), 299 (50), 272 (4), 266 (15), 253
(24), 241 (23), 225 (4), 220 (3), 213 (3), 207 (13), 195 (8), 179 (8), 167
(18), 152 (13), 139 (51), 126 (17), 113 (7), 101 (4), 89 (8), 76 (11), 63
(15), 50 (8).
4.3.2. 8-(4-Methoxyphenyl)-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzox-
azine-1-one (4b). Similar treatment of 8-(4-methoxyphenyl)-4H-
[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-thione (3b) (50.0 mg,
0.160 mmol) with copper powder (1.02 mg, 0.016 mmol) in toluene

5442
A.A. Berezin et al. / Tetrahedron 67 (2011) 5437e5443
4.4. Thionation of 8-substituted 4H-[1,2,4]thiadiazolo[3,4-c]
[1,4]benzoxazin-1-ones
(Ar CH), 127.2 (Ar CH), 126.4 (Cq), 118.3 (Ar CH), 117.7 (Ar CH),
65.4 (CH2O); m/z (EI): 334 (Mþþ2, 41%), 332 (Mþ, 100), 286 (3), 268
(7), 260 (31), 256 (7), 232 (11), 228 (11), 200 (9), 174 (4), 164 (6),
152 (5), 148 (6), 139 (25), 126 (5), 114 (9), 99 (3), 87 (3), 75 (6), 69 (4),
63 (6), 51 (2).
4.4.1. 8-Bromo-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzoxazine-1-
thione (5a) (typical procedure, see Scheme 5). To a solution of 8-
bromo-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzoxazin-1-one
(4a)
(100 mg, 0.351 mmol) in xylene (2 mL) was added P2S5 (38.9 mg,
0.175 mmol). The reaction mixture was then allowed to stir at ca.
140 ꢀC for 12 h and then cooled to ca. 20 ꢀC. The solvent was re-
moved in vacuo and the residue dissolved in DCM (5 mL), adsorbed
onto silica and chromatographed (DCM) to give the title compound
5a (94 mg, 89%) as pale yellow needles, mp (DSC) onset: 203 ꢀC,
peak max: 205 ꢀC (from chloroform), Rf (DCM) 0.67; found: C, 36.0;
H, 1.6; N, 9.2. C9H5BrN2OS2 requires C, 35.9; H, 1.7; N, 9.3%; lmax
4.4.4. 8-(3-Nitrophenyl)-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzox-
azine-1-thione (5d). Similar treatment of 8-(3-nitrophenyl)-4H-
[1,2,4]thiadiazolo[3,4-c][1,4]benzoxazin-1-one
(4d)
(100 mg,
0.306 mmol) with P2S5 (34.0 mg, 0.153 mmol) in xylene (2 mL) at
ca. 140 ꢀC for 12 h gave the title compound 5d (76 mg, 72%) as pale
yellow needles, mp (DSC) onset: 238.6 ꢀC, peak max: 239.4 ꢀC (from
1,2-dichloroethane), Rf (DCM) 0.69; found: C, 52.6; H, 2.6; N, 12.2.
C15H9N3O3S2 requires C, 52.5; H, 2.6; N, 12.2%; lmax (DCM)/nm 252
(DCM)/nm 237 (log
3
3.38), 251 inf (3.25), 288 (2.97), 298 (2.97),
(log 3
3.70), 330 (3.23); nmax/cmꢁ1 3094w, 3084w, 3073w, 3015w
332 (3.26); nmax/cmꢁ1 3105w, 3080w (Ar CH), 2903w, 1638w,
1607w, 1593w, 1553w, 1477s, 1441w, 1420m, 1354w, 1327m, 1294s,
1265m, 1238m, 1223s, 1192s, 1171m, 1121w, 1076m, 1049m, 1022s,
1011m, 968w, 943w, 872m, 866m, 816s, 783m, 777m; dH (300 MHz,
CDCl3) 9.71 (1H, d, J 1.9, H-9), 7.44 (1H, dd, J 8.7,1.9, H-7), 7.07 (1H, d,
J 8.7, H-6), 5.03 (2H, s, CH2O); dC (125 MHz, CDCl3) 195.0 (C]S),
153.0 (Cq), 145.9 (Cq), 132.0 (Ar CH), 126.9 (Cq), 122.1 (Ar CH), 119.4
(Ar CH), 115.0 (Cq), 65.4 (CH2O); m/z (EI): 302 (Mþþ2, 100%), 300
(Mþ, 96), 262 (16), 260 (15), 238 (10), 236 (10), 230 (22), 228 (20),
202 (11), 200 (11), 196 (7), 172 (10), 170 (19), 168 (10), 153 (3), 121
(5), 117 (5), 110 (20), 94 (5), 88 (6), 76 (25), 63 (23), 50 (13).
(Ar CH), 1614w, 1597w, 1558w, 1526m, 1504s, 1477w, 1449w,
1406w, 1352s, 1335s, 1317m, 1308m, 1296s, 1273w, 1242s, 1229s,
1204s, 1179w, 1171w, 1105w, 1088w, 1055m, 1032s, 966w, 928w,
905w, 878m, 856m, 829m, 804m, 785s, 766w; dH (300 MHz, DMSO-
d6) 9.86 (1H, d, J 2.3, H-9), 8.41 (1H, dd, J 2.1, H-20), 8.23 (1H, ddd,
J 8.3, 2.3, 0.9, Ar H), 8.09 (1H, ddd, J 7.7, 1.7, 0.9, Ar H), 7.85 (1H, dd,
J 8.5, 2.3, H-7), 7.80 (1H, dd, J 8.3, 8.3, H-50), 7.43 (1H, d, J 8.5, H-6),
5.32 (2H, s, CH2O); dC (125 MHz, DMSO-d6) 194.6 (C]S), 154.6 (Cq),
148.4 (Cq), 146.9 (Cq), 140.2 (Cq), 132.5 (Ar CH), 131.7 (Cq), 130.6 (Ar
CH), 127.6 (Ar CH), 126.3 (Cq), 122.1 (Ar CH), 120.5 (Ar CH), 118.5 (Ar
CH), 116.8 (Ar CH), 65.0 (CH2O); m/z (EI): 343 (Mþ, 100%), 303 (6),
279 (7), 271 (25), 243 (12), 239 (13), 225 (2), 211 (4), 197 (6), 193 (9),
171 (3), 164 (15), 153 (6), 139 (39), 126 (8), 114 (5), 101 (2), 89 (4), 76
(7), 63 (9), 51 (4).
4.4.2. 8-(4-Methoxyphenyl)-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzox-
azine-1-thione (5b). Similar treatment of 8-(4-methoxyphenyl)-
4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzoxazin-1-one (4b) (100 mg,
0.320 mmol) with P2S5 (35.6 mg, 0.160 mmol) in xylene (2 mL) at
ca. 140 ꢀC for 12 h gave the title compound 5b (82 mg, 78%) as col-
ourless cotton needles, mp (DSC) onset: 142 ꢀC, peak max: 143 ꢀC
(from 1,2-dichloroethane), Rf (DCM) 0.69; found: C, 58.6; H, 3.6; N,
8.4. C16H12N2O2S2 requires C, 58.5; H, 3.7; N, 8.5%; lmax (DCM)/nm
4.5. X-ray crystallographic studies
Data were collected on an Oxford-Diffraction Supernova dif-
fractometer, equipped with a CCD area detector utilizing Mo K
a
3.59), 273 inf (3.48), 333 (3.14); nmax/cmꢁ1 3005w (Ar
radiation (
l¼0.71073 A). Suitable crystals were attached to glass
ꢀ
256 (log
3
CH), 2945w, 2828w, 1607w, 1597w, 1585w, 1572w, 1524w, 1493s,
1468w, 1439m, 1408w, 1364w, 1333m, 1308m, 1292m, 1277m,
1254m, 1242m, 1229s, 1202m, 1180s, 1136w, 1117w, 1049m, 1020m,
966w, 955w, 930w, 881m, 854w, 831m, 816s, 806m, 783m, 752m;
dH (300 MHz, CDCl3) 9.73 (1H, d, J 2.1, H-9), 7.54 (2H, d, J 8.9, Ar H),
7.49 (1H, dd, J 8.5, 2.3, H-7), 7.21 (1H, d, J 8.5, H-6), 6.99 (2H, d, J 8.9,
Ar H), 5.04 (2H, s, CH2O), 3.85 (3H, s, CH3O); dC (75 MHz, CDCl3)
195.0 (C]S), 159.3 (Cq), 153.6 (Cq), 145.4 (Cq), 135.6 (Cq), 131.7 (Cq),
127.8 (Ar CH), 126.8 (Ar CH), 126.2 (Cq), 118.0 (Ar CH), 117.2 (Ar CH),
114.3 (Ar CH), 65.3 (CH2O), 55.3 (CH3O); m/z (EI): 328 (Mþ, 100%),
313 (7), 282 (3), 264 (10), 256 (20), 237 (8), 228 (5), 224 (18), 209
(7), 196 (4), 185 (3), 164 (5), 157 (4), 153 (6), 140 (3), 127 (9), 114 (2),
101 (2), 89 (2), 77 (3), 63 (3), 51 (2).
fibres using paratone-N oil and transferred to a goniostat where
they were cooled for data collection. Unit cell dimensions were
determined and refined by using 14,618 (3.19ꢃ
q
ꢃ28.65ꢀ) and 1944
(3.00ꢃ
q
ꢃ28.60ꢀ) reflections for compounds 3a and 4a, respectively.
Empirical absorption corrections (multi-scan based on symmetry-
related measurements) were applied using CrysAlis RED soft-
ware.10 The structures were solved by direct methods using SIR9211
and refined on F2 using full-matrix least squares using SHELXL97.12
Software packages used: CrysAlis CCD10 for data collection, CrysAlis
RED10 for cell refinement and data reduction, WINGX for geometric
calculations13 and DIAMOND14 for molecular graphics. The non-H
atoms were treated anisotropically, whereas the hydrogen atoms
were placed in calculated, ideal positions and refined as riding on
their respective carbon atoms.
4.4.3. 8-(4-Chlorophenyl)-4H-[1,2,4]thiadiazolo[3,4-c][1,4]benzoxazine-
1-thione (5c). Similar treatment of 8-(4-chlorophenyl)-4H-[1,2,4]
thiadiazolo[3,4-c][1,4]benzoxazin-1-one (4c) (100 mg, 0.316 mmol)
with P2S5 (35.1 mg, 0.158 mmol) in xylene (2 mL) at ca. 140 ꢀC for 12 h
gave the title compound 5c (79 mg, 75%) as violet prisms, mp
(DSC) onset: 193 ꢀC, peak max: 194 ꢀC (from 1,2-dichloroethane), Rf
(DCM) 0.80; found: C, 54.2; H, 2.7; N, 8.4. C15H9ClN2OS2 requires C,
4.5.1. Crystal refinement data for compound 3a. C9H5BrN2O2S,
M¼285.12, monoclinic, space group P21/n, a¼10.4815(2),
3
ꢀ
ꢀ
ꢀ
b¼7.3094(2), c¼12.7848(2) A,
b
¼93.450(2) , V¼977.71(3) A , Z¼4,
T¼100(2) K, rcalcd¼1.937 g cmꢁ3, 2qmax¼54. Refinement of 136 pa-
rameters on 2246 independent reflections out of 19,667 measured
reflections (Rint¼0.0341) led to R1¼0.0175 [I>2 (I)], wR2¼0.0449
s
54.1; H, 2.7; N, 8.4%; lmax (DCM)/nm 253 (log
3
3.64), 332 (3.19); nmax
/
(all data), and S¼1.092 with the largest difference peak and hole of
cmꢁ1 3084w, 3017w (Ar CH), 1618w, 1597m, 1570w, 1547w, 1510w,
1483s, 1449w, 1435w, 1393w, 1369w, 1333m, 1298s, 1248s, 1240s,
1209s, 1182w, 1144w, 1123w, 1094m, 1051m, 1028m, 1009m, 964w,
939w, 893w, 878m, 839w, 826s, 814s, 795m, 787m, 760m; dH
(300 MHz, CDCl3) 9.78 (1H, d, J 2.3, H-9), 7.54 (2H, d, J 8.7, Ar H),
7.51 (1H, dd, J 8.5, 2.3, H-7), 7.43 (2H, d, J 8.7, Ar H), 7.25 (1H, d, J 8.5,
H-6), 5.06 (2H, s, CH2O); dC (125 MHz, CDCl3) 195.2 (C]S), 153.5
(Cq), 146.2 (Cq), 137.8 (Cq), 134.8 (Cq), 133.8 (Cq), 129.1 (Ar CH), 128.1
0.345 and ꢁ0.244 eꢁ3, respectively.
4.5.2. Crystal refinement data for compound 4a. C9H5BrN2O2S,
M¼285.12, orthorhombic, space group P212121, a¼4.5350(2),
3
ꢀ
ꢀ
b¼8.0134(3), c¼25.4590(7) A, V¼925.20(6) A , Z¼4, T¼100(2) K,
rcalcd¼2.047 g cmꢁ3, 2qmax¼54. Refinement of 136 parameters on
1852 independent reflections out of 2821 measured reflections
(Rint¼0.0278) led to R1¼0.0358 [I>2 (I)], wR2¼0.0860 (all data),
s

A.A. Berezin et al. / Tetrahedron 67 (2011) 5437e5443
5443
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and S¼1.048 with the largest difference peak and hole of 0.544 and
ꢁ0.532 eꢁ3, respectively.
Crystallographic data for compounds 3a and 4a have been de-
posited with the Cambridge Crystallographic Data Centre with
deposit numbers CCDC-817083 and CCDC-817084, respectively.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/
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Acknowledgements
ꢁ
ꢁ
The authors wish to thank the Cyprus Research Promotion
Foundation [grant no. YGEIA/BIOS/0308(BE)/16] and the following
organizations in Cyprus for generous donations of chemicals and
glassware: the State General Laboratory, the Agricultural Research
Institute, the Ministry of Agriculture and Biotronics Ltd. Further-
more, we thank the A.G. Leventis Foundation for helping to
establish the NMR facility in the University of Cyprus.
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