Synthesis of asymmetric 3,5-diaryl-4H-1,2,6-thiadiazin-4-ones via Suzuki-Miyaura and Stille coupling reactions

Article abstract of DOI:10.1016/j.tet.2012.06.079

Asymmetric 3,5-diaryl substituted 4H-1,2,6-thiadiazin-4-ones can be prepared from 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1) via a multi-step protocol: selective nucleophilic mono-chloro substitution gives either the mono-methoxy or benzyloxy substituted mono-chlorothiadiazinones that can be phenylated via Suzuki-Miyaura coupling. Subsequent BBr₃ mediated dealkylation gives 3-hydroxy-5-phenyl-4H-1,2,6-thiadiazin-4-one (9) that can be activated by a modified Finkelstein halodehydroxylation via the triflate, enabling further arylation reactions using Suzuki-Miyaura or Stille coupling chemistry.

Full text of DOI:10.1016/j.tet.2012.06.079

Tetrahedron 68 (2012) 7380e7385
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of asymmetric 3,5-diaryl-4H-1,2,6-thiadiazin-4-ones via
SuzukieMiyaura and Stille coupling reactions
*
Heraklidia A. Ioannidou, Panayiotis A. Koutentis
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:
Asymmetric 3,5-diaryl substituted 4H-1,2,6-thiadiazin-4-ones can be prepared from 3,5-dichloro-4H-
1,2,6-thiadiazin-4-one (1) via a multi-step protocol: selective nucleophilic mono-chloro substitution
gives either the mono-methoxy or benzyloxy substituted mono-chlorothiadiazinones that can be
phenylated via SuzukieMiyaura coupling. Subsequent BBr3 mediated dealkylation gives 3-hydroxy-5-
phenyl-4H-1,2,6-thiadiazin-4-one (9) that can be activated by a modified Finkelstein halodehydrox-
ylation via the triflate, enabling further arylation reactions using SuzukieMiyaura or Stille coupling
chemistry.
Received 21 March 2012
Received in revised form 12 June 2012
Accepted 20 June 2012
Available online 28 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
While many 5-substituted derivatives of 3-chloro-4H-1,2,6-
thiadiazin-4-ones have high fungicidal activity,15e18 this applica-
Various oxidized 1,2,6-thiadiazines such as the sulfoxides and,
more importantly, sulfones have received considerable attention in
various areas of applied chemistry including the pharmaceutical,1
agrochemical2 and materials3 sectors. 1,2,6-Thiadiazines that are
not oxidized at sulfur are rare.4,5 Two notable exceptions, 3,5-
dichloro-4H-1,2,6-thiadiazin-4-one (1) and its dicyanomethylene
analogue 2, are potentially useful thiadiazine building blocks.6e14
The former can be readily prepared from dichloromalononitrile
and SCl2, followed by hydrolysis with formic acid, in good overall
yield (78%),6 while the latter from tetracyanoethylene (TCNE) and
SCl2 (Scheme 1).7,8
tion has not prompted extensive synthetic studies. Indeed the
chemistry of the dichlorothiadiazines 1 and 2 remains limited. The
chlorines in 1 and 2 can be successively displaced by a range of
nucleophiles, the second compound requiring more harsh condi-
tions.6,10,11 Furthermore, both dichlorothiadiazines 1 and 2 react
with bisnucleophiles to undergo nucleophilic substitution of the
chlorine and subsequent cyclocondensation reactions at C-4 to give
fused 4H-1,2,6-thiadiazines.10 Interestingly, fused 4H-1,2,6-thia-
diazines are of interest: acenaphtho[5,6-cd][1,2,6]thiadiazine
(3)19,20 and naphtho[1,8-cd:4,5-c0d0]bis([1,2,6]thiadiazine) (4),21 are
examples of ‘extreme quinoids’, that have ambiguous aromatic
character and cyclopenta[1,2,6]thiadiazines 5 and 6,22,23 display
unusual liquid crystalline properties or behave as near infra-red
dyes (Scheme 2).
Scheme 2.
Recently, we demonstrated that 3,5-dichloro-4H-1,2,6-
thiadiazin-4-one (1) undergoes both SuzukieMiyaura and Stille
coupling chemistry to afford symmetrical 3,5-diaryl or heteroaryl
substituted analogues.12 The successful preparation of asymmetrical
Scheme 1.
* Corresponding author. E-mail address: koutenti@ucy.ac.cy (P.A. Koutentis).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.079

H.A. Ioannidou, P.A. Koutentis / Tetrahedron 68 (2012) 7380e7385
7381
diaryl substituted analogues was also achieved via Stille coupling
reactions of non-symmetrical 3,5-dihalo(pseudohalo)-1,2,6-
thiadiazin-4-ones.13 Nevertheless, attempts to selectively prepare
asymmetric diaryl analogues starting from 3,5-dihalo(pseudohalo)-
1,2,6-thiadiazin-4-ones using the SuzukieMiyaura reaction gave, in
all cases, a mixture of mono and bi-arylated systems.13
We now report a successful protecting group strategy that takes
advantage of the facile reaction of 3,5-dichloro-4H-1,2,6-thiadiazin-
4-one (1) with alkoxides that can selectively afford in highyields the
mono-chloro displaced 3-alkoxy-5-chloro-4H-1,2,6-thiadiazin-4-
one. Subsequent arylation, followed by dealkylation and halo-
dehydroxylation affords 3-aryl-5-halo-4H-1,2,6-thiadiazin-4-ones
that can undergo a final Suzuki or Stille coupling to give asym-
metric diarylthiadiazines.
Benzyl groups are known to undergo O to N migration in acidic
medium,24 but the reverse is not known. Not surprisingly, treating
N-benzyl-5-phenyl-1,2,6-thiadiazin-3,4-dione (10) in neat tri-
fluoroacetic acid (TFA) at ca. 90 ꢀC for 24 h gave only recovered
starting material indicating that cleavage or migration (N to O) of
the N-benzyl group under these conditions did not occur. As such,
the protic acid-mediated deprotection of the benzyloxy group had
limitations. Fortunately, the use of BBr3 in DCM at ca. 0 ꢀC for
10 min gave the desired hydroxythiadiazinone 9 in high yield (94%).
The use of BBr3 in DCM at ca. 20 ꢀC for 10 min also demethylated
the methoxy compound 8a smoothly to afford the hydroxy-
thiadiazinone 10 in quantitative yield (Scheme 4).
2. Results and discussion
The selective introduction of an alkoxy group is readily achieved
since on mono-chloride substitution the new alkoxy substituent
mesomerically releases electron density into the thiadiazine ring,
making the ring less electron-deficient and subsequently, less re-
active towards nucleophilic substitution.6,9 The 5-methoxy and 5-
benzyloxy thiadiazinones 7a and 7b were, therefore, readily pre-
pared from 3,5-dichloro-1,2,6-thiadiazin-4-one (1) after treatment
with 1 equiv of either sodium methoxide and sodium benzyloxide,
respectively (Scheme 3). Both compounds 7a and 7b, undergo
SuzukieMiyaura coupling with phenylboronic acid to give 3-
methoxy-5-phenyl-4H-1,2,6-thiadiazin-4-one
(8a)
and
3-
benzyloxy-5-phenyl-4H-1,2,6-thiadiazin-4-one (8b) in 90 and 88%
yields, respectively (Scheme 3).
Scheme 4. Reagents and conditions: (i) R¼Me or Bn, BBr3 (1.2 equiv), DCM, rt, 10 min,
100%; (ii) Tf2O (2 equiv), Et3N (1.1 equiv), DCM, 0e10 ꢀC, 30 min, 95%; (iii) Hal¼Cl,
BnEt3NCl (1.2 equiv), acetone, 20e56 ꢀC, 95%; Hal¼Br, Et4NBr (1.2 equiv), acetone,
20e56 ꢀC, 75%; Hal¼I, KI (1.2 equiv), acetone, 20e56 ꢀC, 6 h, 40%.
Scheme 3. Reagents and conditions: (i) R¼Me, Na (1 equiv), MeOH, 0 ꢀC, 15 min, 94%,
R¼Bn, BnOH (1.5 equiv), NaH (2 equiv), THF, rt, 8 h, 88%; (ii) PhB(OH)2, Pd(OAc)2
(5 mol %) Na2CO3 (1.5 equiv), dioxane/H2O (5:3), 1.5 h, 20e100 ꢀC, R¼Me, 90%, R¼Bn,
88%.
Having the hydroxythiadiazinone 10 in high yield, we attempted
the direct synthesis of the chloro or the bromo analogues 12a and
12b. Treating the hydroxythiadiazinone 10 with either POCl3, SOCl2,
POBr3 or SOBr2 at room temperature led to mainly recovered
starting material, while on heating, traces of the desired products
could be detected but mainly ring-opening and decomposition
were observed. Nevertheless, the synthesis of the halo derivatives
could be achieved via a modified Finkelstein reaction,13 which first
required the synthesis of the triflate and then subsequent conver-
sion to the halogen. As such, treatment of the hydroxythiadiazinone
10 with trifluoromethanesulfonic anhydride in the presence of
triethylamine gave the 3-phenyl-5-triflate thiadiazinone 11 in 95%
yield, which after treatment with tetralkylammonium halides or KI
afforded in high yields the 3-halo-5-phenylthiadiazinones 12a
(Hal¼Cl), 12b (Hal¼Br) and 12c (Hal¼I) (Scheme 4).
Initial attempts to debenzylate the 3-benzyloxy compound 7b to
access the desired 3-hydroxy-5-phenyl-4H-1,2,6-thiadiazin-4-one
(9) included a variety of conditions: (i) reductive cleavage using
Pd/C and H2, (ii) DIBAL and (iii) oxidative cleavage using DDQ or Br2.
All these attempts failed, affording mainly unreacted starting ma-
terial. Treatment with protic or Lewis acids, however, did give some
product. Interestingly, treating the benzyloxythiadiazinone 8b in
neat TFA at 90 ꢀC gave a moderate yield (46%) of the desired
hydroxythiadiazinone 9 together with a second product 10, which
was isolated as yellow needles, mp 126e129 ꢀC (from cyclohexane).
Microanalysis of this compound and mass spectrometry (m/z 296)
indicated the unknown product was an isomer of the benzylox-
ythiadiazinone 8b. 1H and 13C NMR spectroscopic analysis indicated
10 aromatic protons confirming the presence of both the phenyl
rings but more interestingly the signals for the benzylic methylene
CH2 had shifted from dH 5.39 and dC 60.1 ppm in the starting ben-
zyloxythiadiazinone 8b to dH 5.01 and dC 49.4 ppm in the new
product, tentatively indicating that they were now bound to a less
electronegative heteroatom. The above data suggested that the
benzyl group had undergone an O to N migration to give N-benzyl-
5-phenyl-1,2,6-thiadiazin-3,4-dione (10) (48%).
2.1. SuzukieMiyaura and Stille reactions
A preliminary study of the SuzukieMiyaura reaction included
our previously optimized Suzuki conditions for the reaction of 3,5-
dichloro-4H-1,2,6-thiadiazin-4-one (1): RB(OH)2 (2.2 equiv),
Pd(OAc)2 (5 mol %), Na2CO3 (2 equiv) in dioxane/H2O (0.5:0.3 mL)
at ca. 100 ꢀC.12 Using this protocol the triflate 11 suffered hydrolysis
to give back the hydroxythiadiazine 10; fortunately both the chloro
and bromo analogues 12a and 12b successfully afforded the desired
diaryl products 13 in good yields (Table 1).

7382
H.A. Ioannidou, P.A. Koutentis / Tetrahedron 68 (2012) 7380e7385
Table 1
chloro and bromo analogues 12a and 12b, it was not chosen for
further derivatisation. This difference in reactivity (OTf>I>Br>Cl)
was similar to our previous observations,13 and in general was
maintained when the more electron rich or electron-deficient
stannyl reagents 1-methyl-2-(tributyltin)pyrrole or 2-(tributyltin)
furan, respectively, were used (Table 2). In general, the highest
yields were obtained with the chlorothiadiazine 12a, while signif-
icantly shorter reaction times were obtained with the triflate 11.
Suzuki reaction of 3-halo-5-phenyl-4H-1,2,6-thiadiazin-4-ones 12a (Hal¼Cl) and
12b (Hal¼Br) (0.22 mmol) with RB(OH)2 (1 equiv), Pd(OAc)2 (5 mol %) and Na2CO3
(1.5 equiv) in dioxane/H2O (0.5:0.3 mL) at ca. 100 ꢀ
C
3. Conclusions
A multi-step protocol for the SuzukieMiyaura mediated asym-
metric 3,5-diarylation of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one
has been developed. The protocol takes advantage of the facile
and mono selective introduction of a methoxy or benzyloxy sub-
stituent that after subsequent arylation can be dealkylated in high
yield to give the arylhydroxythiadiazinone. Conversion of the
arylhydroxythiadiazinone into a range of 3-halo/pseudohalo 5-
aryl-4H-1,2,6-thiadiazin-4-ones was achieved via a modified Fin-
kelstein reaction. These can undergo a second arylation using either
SuzukieMiyaura or Stille coupling reactions to afford the target
compounds in high yield.
Hal
Ar
Time (h)
Yields (%)
Br
Cl
Br
Cl
Br
Cl
Br
Cl
2-MeOC6H4
2-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-O2NC6H4
3-O2NC6H4
4-ClC6H4
5.0
6.0
5.5
6.3
3.5
3.6
3.5
4.0
13a (79)
13a (78)
13b (91)
13b (81)
13c (83)
13c (78)
13d (77)
13d (80)
4-ClC6H4
The reactions with arylboronic acid supporting electron-donating
substituents (2 and 4-MeO) gave marginally longer reaction times
compared to those with electron-withdrawing substituents (Cl and
NO2). Furthermore, no significant difference could be ascertained
between the reactivity of the bromo or chlorothiadiazinones.
4. Experimental
4.1. General procedures
In light of the successful preparation of asymmetrically
substituted diaryl analogues using the SuzukieMiyaura protocol
we then examined the reactivity of the newly synthesized triflate
and halo thiadiazinones 11, 12a, 12b and 12c towards our typical
Stille coupling conditions: stannyl reagent (1 equiv) and
Pd(Ph3P)2Cl2 (5 mol %) in MeCN at ca. 82 ꢀC.12 Initial studies using
2-(tributyltin)thiophene led to moderate to high yields of 3-
Reactions were protected by CaCl2 drying tubes. Anhydrous
Na2SO4 was used for drying organic extracts and all volatiles were
removed under reduced pressure. All reaction mixtures and col-
umn 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).25 Melting points were determined using
a PolyTherm-A, Wagner & Munz, Koefler-Hotstage Microscope
apparatus. Decomposition points (decomp.) and mp >250 ꢀC were
determined using a TA Instruments DSC Q1000 with samples her-
metically 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. A CEM Discover Microwave
Reactor was used for microwave experiments. UV spectra were
obtained using a PerkineElmer Lambda-25 UV/vis spectropho-
tometer and inflections are identified by the abbreviation ‘inf’. IR
spectra were recorded on a Shimadzu FTIR-NIR Prestige-21 spec-
trometer with Pike Miracle Ge ATR accessory and strong, medium
and weak peaks are represented by s, m and w, respectively. 1H and
13C NMR spectra were recorded on a Bruker Avance 500 machine
(at 500 and 125 MHz, respectively). Deuterated solvents were used
for homonuclear lock and the signals are referenced to the deu-
terated solvent peaks. Low-resolution (EI) mass spectra were
recorded on a Shimadzu Q2010 GCeMS with direct inlet probe.
Microanalysis was performed at London Metropolitan University
on a PerkineElmer 2400 Series II CHN Analyzer. 3,5-Dichloro-4H-
1,2,6-thiadiazn-4-one (1) was prepared according to literature
procedures.6
phenyl-5-(thien-2-yl)-4H-1,2,6-thiadiazin-4-one
(13e)
(12a,
Cl¼99%, tR¼4 h; 12b, Br¼89%, tR¼3.5 h; 12c, I¼80%, tR¼1.5; 11,
OTf¼92%, tR¼0.5 h) (see Table 2).
Table 2
Stille reactions of 3-halo and 3-triflate 5-phenyl-4H-1,2,6-thiadiazin-4-ones 12 and
11 (0.22 mmol) with ArSnBu3 (1 equiv) and Pd(Ph3P)2Cl2 (5 mol %) in MeCN at ca.
82 ꢀC
11, 12aec
Ar
Time (h)
Yields (%)
12a (X¼Cl)
12b (X¼Br)
12c (X¼I)
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
N-Me-pyrrol-2-yl
N-Me-pyrrol-2-yl
N-Me-pyrrol-2-yl
Fur-2-yl
Fur-2-yl
Fur-2-yl
4.0
3.5
1.5
0.5
3.5
3.0
0.8
3.8
3.6
0.7
13e (99)
13e (89)
13e (80)
13e (92)
13f (77)
13f (86)
13f (88)
13g (100)
13g (88)
13g (94)
11 (X¼OTf)
12a (X¼Cl)
12b (X¼Br)
11 (X¼OTf)
12a (X¼Cl)
12b (X¼Br)
11 (X¼OTf)
4.2. 3-Chloro-5-methoxy-4H-1,2,6-thiadiazin-4-one (7a)
To a flask containing dry MeOH (8 mL) under argon at 0 ꢀC, was
added sodium (128.8 mg, 5.6 mmol). To the resulting solution, 3,5-
dichloro-4H-1,2,6-thiadiazin-4-one (1) (1.00 g, 5.6 mmol) was
added and the mixture left at this temperature until no starting ma-
terial remained (TLC). The mixture was then adsorbed onto silica and
chromatography (hexane/DCM, 1:1) gave the title compound 7a
Worthy of note was the fast reaction times observed with triflate
11. Furthermore, the iodothiadiazinone 12c, while it gave relatively
fast reaction times (1.5 h) gave the lowest yield of the desired
product 13e (80%). Owing to the low-yielding preparation of the
iodothiadiazinone 12c (40%, see Scheme 4) in comparison with the

H.A. Ioannidou, P.A. Koutentis / Tetrahedron 68 (2012) 7380e7385
7383
(940 mg, 94%) as yellow needles, mp 68e69 ꢀC (from cyclohexane),
908w, 885w, 827w, 814w, 802w; dH (500 MHz; CDCl3) 8.14e8.12
(2H, m, Ph H), 7.50e7.35 (8H, m, Ph H), 5.39 (2H, s, OCH2); dC
(125 MHz; CDCl3) 161.3 (s), 157.8 (s), 157.7 (s), 134.9 (s), 134.4 (s),
130.6 (d), 128.7 (d), 128.6 (d), 128.5 (d), 128.4 (d), 128.2 (d), 69.1 (t,
OCH2); m/z (EI) 296 (Mþ, 4%), 268 (2), 165 (2), 135 (6), 107 (4), 105
(9), 103 (17), 91 (100), 76 (9), 74 (5), 65 (12), 51 (6).
(lit.,6 74e75 ꢀC), Rf 0.26 (hexane/DCM,1:1); lmax (DCM)/nm 278 (log
3.0), 344 (3.33); nmax/cmꢁ1 2997w, 2938w, 2845w, 1649s (C]O),
1520m, 1456w, 1447w, 1331m, 1233w, 1211m, 1182w, 991s, 955m,
854m, 804m; dH (500 MHz; CDCl3) 4.01 (3H, s, OCH3); dC (125 MHz;
CDCl3) 157.7 (s),156.4 (s),147.7(s), 55.4(q, OCH3);m/z (EI)180(Mþþ2,
35%), 178 (Mþ, 92), 150 (27), 148 (72), 123 (10), 121 (28), 112 (47), 95
(36), 93 (100), 89 (51), 86 (13), 74 (58), 61 (20), 58 (35), 54 (40).
3
4.6. 2-Benzyl-5-phenyl-2H-1,2,6-thiadiazine-3,4-dione (10) and
3-hydroxy-5-phenyl-4H-1,2,6-thiadiazin-4-one (9) (using TFA)
4.3. 3-(Benzyloxy)-5-chloro-4H-1,2,6-thiadiazin-4-one (7b)
A
stirred solution of 3-(benzyloxy)-5-phenyl-4H-1,2,6-
To a stirred solution of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one
(1) (1.00 g, 5.6 mmol) in THF (8 mL) at ca. 20 ꢀC, was added NaH
(268.8 mg, 11.2 mmol) and BnOH (0.87 mL, 8.4 mmol) and the re-
action mixture was stirred at rt until no starting material remained
(TLC). The reaction mixture was diluted with DCM, adsorbed onto
silica and chromatographed (1:1, hexane/DCM) to give the title
compound 7b (1.25 g, 88%) as pale yellow plates, mp 141e142 ꢀC
(from cyclohexane), Rf 0.38 (hexane/DCM, 1:1); (found: C, 47.20; H,
2.72; N, 10.99. C10H7ClN2O2S requires C, 47.16; H, 2.77; N, 11.00%);
thiadiazin-4-one (8b) (1.00 g, 3.4 mmol) in TFA (4 mL) was heated
at ca. 90 ꢀC until no starting material remained (TLC). The reaction
mixture allowed to cool to ca. 20 ꢀC, diluted with H2O (10 mL) and
then extracted (DCM, 3ꢂ20 mL). The organic extracts were com-
bined, dried (Na2SO4), filtered and adsorbed onto silica. Chroma-
tography (hexane/DCM, 1:4) gave the title compound 10 (484 mg,
48%) as yellow needles, mp 126e129 ꢀC (from cyclohexane), Rf 0.23
(hexane/DCM, 1:4); (found: C, 65.02; H, 4.07; N, 9.56. C16H12N2O2S
requires C, 64.85; H, 4.08; N, 9.45%); lmax (DCM)/nm 229 (log
3.15), 279 inf (2.83), 304 (3.07), 391 (3.15); nmax/cmꢁ1 3030w (Ar
CH), 1650s and 1649s (C]O), 1491w, 1477w, 1456w, 1435m, 1362w,
1331m, 1312m, 1288w, 1207w, 1159w, 1128w, 1078w, 1036m, 999w,
978w, 934w, 905m, 876w, 847w, 826m, 800w, 760s; dH (500 MHz;
CDCl3) 7.96e7.94 (2H, m, Ph H), 7.47e7.40 (8H, m, Ph H), 5.01 (2H, s,
NCH2); dC (125 MHz; CDCl3) 170.5 (s), 158.3 (s), 150.0 (s), 133.9 (s),
133.3 (s), 130.4 (d), 129.3 (d), 129.22 (d), 129.19 (d), 128.4 (d), 128.3
(d), 49.4 (t, OCH2); m/z (EI) 296 (Mþ, 5%), 149 (2), 135 (17), 107 (5),
105 (10), 103 (10), 91 (100), 77 (13), 65 (10), 51 (8). Further elution
3
lmax (DCM)/nm 278 (log
3.06), 343 (3.29); nmax/cmꢁ1 3271w (Ar
3
CH), 2835w, 1645s (C]O), 1522m, 1499w, 1454w, 1389w, 1319s,
1250w, 1219w, 1194m, 958s, 922m, 853w, 841w, 816m, 756m,
725m, 704m; dH (500 MHz; CDCl3) 7.45e7.43 (2H, m, Ph H),
7.39e7.35 (3H, m, Ph H), 5.38 (2H, s, OCH2); dC (125 MHz; CDCl3)
157.6 (s), 155.5 (s), 147.8 (s), 134.1 (s), 128.8 (d), 128.7 (d), 128.6 (d),
70.0 (t, OCH2); m/z (EI) 254 (Mþ, 3%), 165 (3), 105 (5), 92 (8), 91
(100), 77 (2), 65 (12), 51 (3).
4.4. 3-Methoxy-5-phenyl-4H-1,2,6-thiadiazin-4-one (8a)
(t-BuOMe/EtOH,
9:1)
gave
3-hydroxy-5-phenyl-4H-1,2,6-
thiadiazin-4-one (9) (322 mg, 46%) as yellow plates, mp
120e122 ꢀC (from cyclohexane/DCM), Rf 0.28 (t-BuOMe/EtOH, 9:1);
(found: C, 52.48; H, 2.91; N, 13.57. C9H6N2O2S requires C, 52.42; H,
To
a
stirred solution of 3-chloro-5-methoxy-4H-1,2,6-
thiadiazin-4-one (7a) (1.00 g, 5.6 mmol) in dioxane/H2O (5:3,
8 mL) at ca. 20 ꢀC, was added PhB(OH)2 (819 mg, 6.7 mmol), Na2CO3
(890 mg, 8.4 mmol) and Pd(OAc)2 (62.8 mg, 0.28 mmol, 5 mol %).
The reaction mixture was then heated at ca. 100 ꢀC until no starting
material remained (TLC). On cooling to ca. 20 ꢀC the reaction mix-
ture was then diluted with DCM (20 mL) and extracted (H2O). The
organic extracts were combined, dried (Na2SO4), filtered and
adsorbed onto silica. Chromatography (hexane/DCM, 1:1) gave the
title compound 8a (1.11 g, 90%) as yellow needles, mp 73e75 ꢀC
(from pentane), Rf 0.26 (hexane/DCM, 1:1); (found: C, 54.63; H,
3.76; N, 12.64. C10H8N2O2S requires C, 54.53; H, 3.66; N, 12.72%);
2.93; N, 13.58%); lmax (DCM)/nm 230 (log
3
3.01), 241 (2.80), 307
(3.13), 323 inf (3.04), 361 (3.16); nmax/cmꢁ1 3248br w (OH), 1612s
and 1601s (C]O), 1537w, 1491w, 1458w, 1422w, 1379s, 1323w,
1294s, 1223m, 1183m, 1142m, 1076w, 1034w, 947m, 928w, 891w,
835s, 802w, 760w; dH (500 MHz; CDCl3) OH peak missing
8.23e8.21 (2H, m, Ph H), 7.49e7.48 (3H, m, Ph H); dC (125 MHz;
CDCl3) 160.7 (s), 160.0 (s), 154.9 (s), 133.8 (s), 131.0 (d), 128.5 (d),
128.4 (d); m/z (EI) 206 (Mþ, 56%), 135 (14), 121 (3), 104 (100), 91 (4),
77 (36), 75 (55), 63 (4), 51 (17).
lmax (DCM)/nm 235 (log
3
3.55), 270 (2.21); nmax/cmꢁ1 3046w (Ar
4.7. 3-Hydroxy-5-phenyl-4H-1,2,6-thiadiazin-4-one (9)
CH), 2949w, 2936w, 2859w, 1644m (C]O), 1629s, 1600w, 1531m,
1453w, 1438w, 1348s, 1335m, 1314w, 1283m, 1197w, 1159w, 1139s,
1073w, 1004w, 990s, 965w, 951w, 914w, 861w, 821m, 801w, 746s;
dH (500 MHz; CDCl3) 8.13e8.11 (2H, m, Ph H), 7.45 (3H, br s, Ph H),
4.00 (3H, s, OCH3); dC (125 MHz; CDCl3) 161.3 (s), 158.7 (s), 157.5 (s),
134.3 (s), 130.6 (d), 128.6 (d), 128.2 (d), 54.7 (q, OCH3); m/z (EI) 206
(Mþ, 47%),169 (4), 135 (13), 111 (5), 104 (80), 97 (8), 85 (9), 81 (5), 77
(32), 75 (45), 71 (12), 69 (13), 64 (13), 57 (20), 51 (17).
(using BBr3)
To
a
stirred solution of 3-methoxy-5-phenyl-4H-1,2,6-
thiadiazin-4-one (8a) (1.00 g, 4.5 mmol) [or 3-benzyloxy-5-
phenyl-4H-1,2,6-thiadiazin-4-one (8b) (1.30 g, 4.5 mmol)] in DCM
(4 mL) at ca. 0 ꢀC, was added BBr3 (512
mL, 5.4 mmol) and the
mixture was kept at this temperature until no starting material
remained (TLC). The reaction mixture was then extracted (H2O) and
the organic extracts were combined, dried (Na2SO4) and filtered to
afford the title compound 9 (928 mg, 100%) as yellow plates, mp
120e122 ꢀC (from cyclohexane/DCM), Rf 0.28 (t-BuOMe/EtOH, 9:1)
identical to that described above.
4.5. 3-(Benzyloxy)-5-phenyl-4H-1,2,6-thiadiazin-4-one (8b)
Similar
treatment
of
3-(benzyloxy)-5-chloro-4H-1,2,6-
thiadiazin-4-one (7b) (1.40 g, 5.6 mmol) with PhB(OH)2 (819 mg,
6.7 mmol), Na2CO3 (890 mg, 8.4 mmol) and Pd(OAc)2 (62.8 mg,
0.28 mmol) gave the title compound 8b (1.46 g, 88%) as yellow
needles, mp 126e128 ꢀC (from cyclohexane), Rf 0.38 (hexane/DCM,
1:1); (found: C, 65.00; H, 4.08; N, 9.61. C16H12N2O2S requires C,
4.8. 3-Phenyl-5-trifluoromethanesulfonoxy-4H-1,2,6-
thiadiazin-4-one (11)
To a stirred mixture of 3-hydroxy-5-phenyl-4H-1,2,6-thiadiazin-
4-one (9) (1.00 g, 4.8 mmol) in DCM (4 mL) at ca. 0 ꢀC was added
64.85; H, 4.08; N, 9.45%); lmax (DCM)/nm 230 (log 3.06), 238 inf
3
(2.80), 306 (3.23), 354 (3.28); nmax/cmꢁ1 3061w, 3030w and 3001w
(Ar CH), 2955w, 1632s and 1622s (C]O), 1601w, 1585w, 1526s,
1497w, 1489w, 1454w, 1427w, 1383m, 1331s, 1306s, 1267s, 1244w,
1210w, 1125s, 1082w, 1076w, 1030w, 1015w, 999w, 965s, 943m,
Et3N (736 mL, 5.3 mmol) and then Tf2O (1.60 mL, 9.6 mmol) and the
reaction left to warm to ca. 10 ꢀC until no starting material
remained (TLC). The reaction mixture was then diluted (DCM) and
extracted (H2O). The organic layer was dried (Na2SO4), filtered and

7384
H.A. Ioannidou, P.A. Koutentis / Tetrahedron 68 (2012) 7380e7385
adsorbed onto silica. Chromatography (hexane/DCM, 7:3) gave the
title compound 11 (1.54 g, 95%) as yellow plates, mp 59e61 ꢀC
(from cyclohexane), Rf 0.41 (hexane/DCM, 7:3); (found: C, 35.60; H,
1.48; N, 8.25. C10H5F3N2O4S2 requires C, 35.50; H, 1.49; N, 8.28%);
DCM), Rf 0.33 (hexane/DCM, 7:3); (found: C, 34.25; H, 1.63; N, 8.91.
C9H5IN2OS requires C, 34.19; H, 1.59; N, 8.86%); lmax (DCM)/nm 233
(log
3
2.83), 247 inf (2.71), 261 inf (2.65), 341 (2.95); nmax/cmꢁ1
3069w (Ar CH), 1630s (C]O), 1591w, 1483w, 1464w, 1433m, 1321w,
1292m, 1258w, 1221w, 1188w, 1161m, 1134w, 1101w, 1074w, 1032w,
999w, 984w, 935w, 874w, 849w, 822w, 793m; dH (500 MHz; CDCl3)
8.17e8.15 (2H, m, Ph H), 7.52e7.45 (3H, m, Ph H); dC (125 MHz;
CDCl3) 160.4 (s),153.0 (s),133.9 (s),133.5 (s),131.9 (d),129.2 (d),128.4
(d); m/z (EI) 316 (Mþ,100%), 213 (22),189 (35),185 (33),162 (26),135
(38), 127 (10), 103 (54), 86 (54), 76 (31), 63 (6), 58 (6), 51 (22).
lmax (DCM)/nm 231 (log
2.89), 258 (2.86), 328 (3.29); nmax/cmꢁ1
3
3073w (Ar CH), 1730w, 1686w, 1645m (C]O), 1427m, 1331w,
1285w, 1244m, 1227s, 1204m, 1175m, 1125m, 1086w, 1070w,
1030m, 999w, 945w, 935w, 845m; dH (500 MHz; CDCl3) 8.23 (2H,
dd, J 8.5, 1.5, Ph H), 7.56 (1H, ddd, J 7.0, 1.5, 1.5, Ph H), 7.50 (2H, dd, J
8.5, 7.0, Ph H); dC (125 MHz; CDCl3) 163.2 (s), 159.6 (s), 149.1 (s),
132.8 (s), 132.5 (d), 129.2 (d), 128.6 (d), 118.4 (q, 1JCF 318.8, CF3); m/z
(EI) 338 (Mþ, 64%), 269 (2), 205 (5), 177 (29), 149 (13), 143 (45), 134
(49), 115 (18), 103 (40), 91 (5), 77 (22), 69 (100), 51 (15).
4.12. 3-(2-Methoxyphenyl)-5-phenyl-4H-1,2,6-thiadiazin-4-
one (13a); (typical procedure)
4.9. 3-Chloro-5-phenyl-4H-1,2,6-thiadiazin-4-one (12a)
To a stirred solution of 3-bromo-5-phenyl-4H-1,2,6-thiadiazin-
4-one (12b) (50.0 mg, 0.19 mmol) in dioxane/H2O (0.5:0.3 mL) at
ca. 20 ꢀC, was added 2-methoxyphenylboronic acid (28.9 mg,
0.19 mmol), Na2CO3 (30.0 mg, 0.29 mmol) and Pd(OAc)2 (2.1 mg,
9.5ꢂ10ꢁ3 mmol) and the mixture was heated at reflux until no
starting material remained (TLC). On cooling to ca. 20 ꢀC the re-
action mixture was diluted (DCM), extracted (H2O) and the organic
extracts were combined, dried (Na2SO4), filtered and adsorbed onto
silica. Chromatography (hexane/DCM, 1:1) gave the title compound
13a (44 mg, 79%) as yellow plates, mp 71e73 ꢀC (from cyclohex-
ane), Rf 0.39 (hexane/DCM, 1:1); (found: C, 64.77; H, 4.04; N, 9.37.
C16H12N2O2S requires C, 64.85; H, 4.08; N, 9.45%); lmax (DCM)/nm
To a stirred solution of 3-phenyl-5-trifluoromethanesulfonoxy-
4H-1,2,6-thiadiazin-4-one (11) (1.00 g, 3.0 mmol) in acetone (4 mL)
at ca. 20 ꢀC, was added BnEt3NCl (820 mg, 3.6 mmol) and the
mixture was heated at reflux until no starting material remained
(TLC). On cooling to ca. 20 ꢀC the reaction mixture was adsorbed
onto silica and chromatographed (hexane/DCM, 7:3) to give the
title compound 12a (640 mg, 95%) as yellow plates, mp 117e118 ꢀC
(from cyclohexane/DCM), Rf 0.28 (hexane/DCM, 7:3); (found: C,
48.21; H, 2.20; N, 12.56. C9H5ClN2OS requires C, 48.11; H, 2.24; N,
12.47%); lmax (DCM)/nm 233 (log
3
2.87), 252 (2.80), 335 (3.29);
nmax/cmꢁ1 3055w (Ar CH), 1730w, 1655s (C]O), 1638w, 1624s,
1614m, 1601w, 1524w, 1489m, 1443w, 1354w, 1333w, 1321w,
1285w, 1269w,1254w, 1225w, 1179w, 1144w, 1101w, 1076w, 1043m,
914w, 874w, 849w, 797w, 766w; dH (500 MHz; CDCl3) 8.16 (2H, d, J
7.5, Ph H), 7.54e7.46 (3H, m, Ph H); dC (125 MHz; CDCl3) 160.8 (s),
158.0 (s), 153.1 (s), 133.5 (s), 131.8 (d), 129.2 (d), 128.4 (d); m/z (EI)
226 (Mþþ2, 26%), 224 (Mþ, 62), 163 (3), 135 (47), 123 (17), 121 (45),
108 (6), 103 (53), 95 (40), 93 (100), 76 (43), 63 (8), 58 (13), 51 (31).
235 (log
3
3.16), 339 (3.35); nmax/cmꢁ1 3019w (Ar CH), 2959w,
2924w, 2851w, 1638w, 1616m, 1595m, 1584w, 1499w, 1481w,
1462m, 1435m, 1350m, 1288w, 1261m, 1250w, 1238w, 1182w,
1167w, 1115m, 1076w, 1049w, 1024m, 920w, 864w, 851w, 816w,
800w, 768s; dH (500 MHz; CDCl3) 8.19 (2H, dd, J 8.0, 1.5, Ph H),
7.49e7.45 (5H, m, Ph H), 7.08 (1H, dd, J 7.5, 7.5, Ph H), 7.00 (1H, d, J
9.0, Ph H), 3.85 (3H, s, OCH3); dC (125 MHz; CDCl3) 164.9 (s), 163.7
(s), 159.1 (s), 156.8 (s), 134.4 (s), 131.7 (d), 131.1 (d), 130.1 (d), 128.7
(d), 128.3 (d), 125.1 (s), 121.0 (d), 111.3 (d), 55.9 (q, OCH3); m/z (EI)
296 (Mþ, 31%), 265 (12), 193 (5), 165 (33), 135 (100), 119 (10), 108
(6), 103 (30), 91 (21), 77 (27), 63 (9), 51 (11).
4.10. 3-Bromo-5-phenyl-4H-1,2,6-thiadiazin-4-one (12b)
To a stirred solution of 3-phenyl-5-trifluoromethanesulfonoxy-
4H-1,2,6-thiadiazin-4-one (11) (1.00 g, 3.0 mmol) in acetone (4 mL)
at ca. 20 ꢀC, was added Et4NBr (757 mg, 3.6 mmol) and the mixture
was heated at reflux until no starting material remained (TLC). On
cooling to ca. 20 ꢀC the reaction mixture was adsorbed onto silica
and chromatographed (hexane/DCM, 7:3) to give the title com-
pound 12b (606 mg, 75%) as yellow plates, mp 117e118 ꢀC (from
cyclohexane/DCM), Rf 0.28 (hexane/DCM, 7:3); (found: C, 40.24; H,
1.92; N, 10.39. C9H5BrN2OS requires C, 40.17; H, 1.87; N, 10.41%);
4.13. 3-(4-Methoxyphenyl)-5-phenyl-4H-1,2,6-thiadiazin-4-
one (13b)
Similar treatment of 3-bromo-5-phenyl-4H-1,2,6-thiadiazin-4-
one (12b) (50.0 mg, 0.19 mmol) with 4-methoxyphenylboronic
acid (28.9 mg, 0.19 mmol) gave the title compound 13b (51.2 mg,
91%) as yellow needles, mp 84e86 ꢀC (from cyclohexane), Rf 0.31
(hexane/DCM, 1:1); (found: C, 64.93; H, 4.12; N, 9.41. C16H12N2O2S
lmax (DCM)/nm 232 (log
3
2.93), 250 (2.80), 334 (3.27); nmax/cmꢁ1
requires C, 64.85; H, 4.08; N, 9.45%); lmax (DCM)/nm 243 (log 3.13),
3
3063w (Ar CH), 1751w, 1695w, 1633s (C]O), 1601w, 1558w, 1541w,
1506w, 1479w, 1435w, 1344w, 1323w, 1296m, 1240w, 1188w,
1167m, 1101w, 1076w, 1034w, 1003m, 991m, 872w, 851w, 839w,
824w, 795m; dH (500 MHz; CDCl3) 8.16 (2H, dd, J 8.5, 1.5, Ph H),
7.54e7.51 (1H, m, Ph H), 7.49e7.45 (2H, m, Ph H); dC (125 MHz;
CDCl3) 160.6 (s), 156.4 (s), 147.7 (s), 133.5 (s), 131.8 (d), 129.2 (d),
128.4 (d); m/z (EI) 270 (Mþþ2, 78%), 268 (Mþ, 80), 167 (78), 165
(80), 139 (82), 137 (88), 135 (100), 108 (14), 103 (100), 91 (17), 86
(20), 76 (75), 63 (14), 58 (21), 51 (46).
365 (3.34), 384 inf (3.16); nmax/cmꢁ1 2922w, 2839w, 1618m, 1603m,
1578w, 1510w, 1468w, 1441w, 1418w, 1348w, 1312w, 1271w, 1254s,
1188m, 1182m, 1152w, 1121w, 1036m, 1013w, 1003w, 864w, 829m,
812w, 797w, 766w; dH (500 MHz; CDCl3) 8.25 (2H, d, J 9.0, Ph H),
8.13 (2H, d, J 7.0, Ph H), 7.48e7.47 (3H, m, Ph H), 6.97 (2H, d, J 9.0, Ph
H), 3.87 (3H, s, OCH3); dC (125 MHz; CDCl3) 165.5 (s), 162.0 (s), 160.3
(s), 159.9 (s), 134.7 (s), 130.92 (d), 130.89 (d), 128.9 (d), 128.2 (d),
127.2 (d),113.6 (d), 55.4 (OCH3); m/z (EI) 296 (Mþ, 56%),165 (45),150
(12), 135 (100), 133 (18), 122 (5), 103 (17), 90 (7), 77 (15), 57 (5).
4.11. 3-Iodo-5-phenyl-4H-1,2,6-thiadiazin-4-one (12c)
4.14. 3-(3-Nitrophenyl)-5-phenyl-4H-1,2,6-thiadiazin-4-one (13c)
To a stirred solution of 3-phenyl-5-trifluoromethanesulfonoxy-
4H-1,2,6-thiadiazin-4-one (11) (1.00 g, 3.0 mmol) in acetone (4 mL)
at ca. 20 ꢀC, was added KI (598 mg, 3.6 mmol) and the mixture was
heated at reflux until no startingmaterial remained (TLC). On cooling
to ca. 20 ꢀC the reaction mixture was adsorbed onto silica and
chromatographed (hexane/DCM, 7:3) to give the title compound 12c
(379 mg, 40%) as yellow plates, mp 98e101 ꢀC (from cyclohexane/
Similar treatment of 3-bromo-5-phenyl-4H-1,2,6-thiadiazin-4-
one (12b) (50.0 mg, 0.19 mmol) with 3-nitrophenylboronic acid
(31.7 mg, 0.19 mmol) gave the title compound 13c (49 mg, 83%) as
yellow needles, mp 164e165 ꢀC (from cyclohexane), Rf 0.36 (hex-
ane/DCM, 1:1); (found: C, 57.71; H, 2.77; N, 13.66. C15H9N3O3S re-
quires C, 57.87; H, 2.91; N, 13.50%); lmax (DCM)/nm 237 (log
3 3.35),
267 inf (3.11), 350 (3.39); nmax/cmꢁ1 3078w (Ar CH), 1612s (C]O),

H.A. Ioannidou, P.A. Koutentis / Tetrahedron 68 (2012) 7380e7385
7385
1578w, 1533s, 1490w, 1483w, 1474w, 1445m, 1350s, 1281m, 1271m,
1098w, 1082w, 1072w, 1020w, 1001w, 916w, 903w, 889w, 851w,
835w, 810w, 789w; dH (500 MHz; CDCl3) 9.08 (1H, s, Ph H), 8.57
(1H, d, J 8.0, Ph H), 8.34 (1H, dd, J 8.2, 1.3, Ph H), 8.17 (2H, d, J 7.8, Ph
H), 7.66 (1H, dd, J 8.0, 8.0, Ph H), 7.53e7.48 (3H, m, Ph H); dC
(125 MHz; CDCl3) 164.8 (s), 161.6 (s), 158.0 (s), 148.1 (s), 135.7 (s),
134.7 (d), 134.0 (s), 131.6 (d), 129.3 (d), 129.0 (d), 128.4 (d), 125.4 (d),
124.0 (d); m/z (EI) 311 (Mþ, 48%), 180 (100), 135 (75), 108 (5), 103
(19), 90 (16), 77 (17), 63 (7), 51 (8).
787w; dH (500 MHz; CDCl3) 8.10e8.08 (2H, m, Ph H), 7.72 (1H, dd, J
4.0, 1.5, pyrrolyl H), 7.47e7.46 (3H, m, Ph H), 6.88 (1H, s, pyrrolyl H),
6.23 (1H, dd, J 3.8, 2.8, pyrrolyl H), 3.97 (3H, s, NCH3); dC (125 MHz;
CDCl3) 163.7 (s), 158.7 (s), 153.7 (s), 135.1 (s), 131.0 (d), 130.5 (d),
128.7 (d),128.2 (d),126.4 (s), 120.2 (d),108.4 (d), 38.6 (q, NCH3); m/z
(EI) 269 (Mþ, 60%), 164 (3), 138 (50), 135 (100), 123 (3), 110 (6), 106
(29), 103 (23), 91 (7), 77 (20), 64 (4), 51 (13).
4.18. 3-(Fur-2-yl)-5-phenyl-4H-1,2,6-thiadiazin-4-one (13g)
4.15. 3-(4-Chlorophenyl)-5-phenyl-4H-1,2,6-thiadiazin-4-
one (13d)
Similar treatment of 3-bromo-5-phenyl-4H-1,2,6-thiadiazin-4-
one (12b) (50.0 mg, 0.19 mmol) with 2-(tributylstannyl)furan
(59.8 mL, 0.19 mmol) gave the title compound 13g (42.9 mg, 88%) as
Similar treatment of 3-bromo-5-phenyl-4H-1,2,6-thiadiazin-4-
one (12b) (50.0 mg, 0.19 mmol) with 4-chlorophenylboronic acid
(29.7 mg, 0.19 mmol) gave the title compound 13d (44 mg, 77%) as
yellow needles, mp 123e126 ꢀC (from cyclohexane), Rf 0.64 (hex-
ane/DCM, 1:1); (found: C, 59.82; H, 3.00; N, 9.27. C15H9ClN2OS re-
yellow needles, mp 68e71 ꢀC (from cyclohexane), Rf 0.50 (hexane/
DCM, 1:1); (found: C, 60.83; H, 3.26; N, 10.87. C13H8N2O2S requires
C, 60.93; H, 3.15; N, 10.93%); lmax (DCM)/nm 242 (log 2.97), 293
3
(2.60), 373 (3.28), 385 inf (3.10); nmax/cmꢁ1 3167w, 3134w and
3109w (Ar CH), 1624s (C]O), 1609w, 1591w, 1560m, 1483s, 1431w,
1389m, 1346m, 1337w, 1273s, 1213w, 1188w, 1173w, 1142w, 1078w,
1036w, 1024s, 1001w, 993w, 926w, 883m, 847s, 806w, 772s, 700s;
dH (500 MHz; CDCl3) 8.16e8.14 (2H, m, Ph H), 7.90 (1H, d, J 3.5, furyl
H), 7.70 (1H, d, J 1.5, furyl H), 7.49e7.47 (3H, m, Ph H), 6.62 (1H, dd, J
3.5, 1.5, furyl H); dC (125 MHz; CDCl3) 162.4 (s), 159.6 (s), 151.1 (s),
147.8 (s), 146.4 (d), 134.5 (s), 131.1 (d), 129.0 (d), 128.3 (d), 120.0 (d),
112.8 (d); m/z (EI) 256 (Mþ, 85%), 135 (46), 125 (100), 103 (16), 93
(11), 77 (19), 70 (10), 64 (7), 51 (10).
quires C, 59.90; H, 3.02; N, 9.31%); lmax (DCM)/nm 239 (log 3.18),
3
250 (3.14), 352 (3.36); nmax/cmꢁ1 3044w (Ar CH), 1622s (C]O),
1595m, 1481w, 1441w, 1398m, 1352m, 1279m, 1267m, 1188w,
1156w, 1094s, 1034w, 1018m, 1005w, 997w, 916w, 854w, 826m,
804w, 783s; dH (500 MHz; CDCl3) 8.18 (2H, d, J 9.0, Ar H), 8.14 (2H,
dd, J 7.8, 1.3, Ph H), 7.51e7.46 (3H, m, Ph H), 7.44 (2H, d, J 8.5, Ar H);
dC (125 MHz; CDCl3) 165.1 (s), 161.0 (s), 159.4 (s), 137.4 (s), 134.4 (s),
132.8 (s), 131.3 (d), 130.4 (d), 128.9 (d), 128.5 (d), 128.3 (d); m/z (EI)
302 (Mþþ2, 17%), 300 (Mþ, 50), 171 (27), 169 (77), 155 (7), 139 (25),
137 (26), 135 (100), 111 (18), 103 (19), 91 (6), 77 (23), 63 (4), 51 (11).
Acknowledgements
4.16. 3-Phenyl-5-(thien-2-yl)-4H-1,2,6-thiadiazin-4-one (13e);
(typical procedure)
The authors thank the Cyprus Research Promotion Foundation
(grant nos. ENISX/0504/08 and NEKYP/0308/02) for financial
support. Furthermore, the authors thank the following organiza-
tions in Cyprus for generous donations of chemicals and glassware:
the State General Laboratory, the Agricultural Research Institute,
the Ministry of Agriculture, MedoChemie Ltd and Biotronics Ltd.
Finally, we thank the A. G. Leventis Foundation for helping to es-
tablish the NMR facility in the University of Cyprus.
To a stirred solution of 3-bromo-5-phenyl-4H-1,2,6-thiadiazin-
4-one (12b) (50.0 mg, 0.19 mmol) in MeCN (2 mL) at ca. 20 ꢀC, was
added 2-(tributyltin)thiophene (60.3 mL, 0.19 mmol) and
Pd(Ph3P)2Cl2 (6.7 mg, 9.5ꢂ10ꢁ3 mmol) and the reaction was heated
at reflux until no starting material remained (TLC). On cooling to ca.
20 ꢀC the reaction mixture was adsorbed onto silica and chroma-
tographed (hexane/DCM, 1:1) to give the title compound 13e
(46 mg, 89%) as yellow needles, mp 104e106 ꢀC (from cyclohex-
ane), Rf 0.66 (hexane/DCM, 1:1); (found: C, 57.34; H, 3.01; N, 10.19.
C13H8N2OS2 requires C, 57.33; H, 2.96; N, 10.29%); lmax (DCM)/nm
References and notes
1. Breining, T.; Cimpoia, A. R.; Mansour, T. S.; Cammack, N.; Hopewell, P.; Ashman,
C. Heterocycles 1995, 41, 87e94.
2. McKendry, L. H.; Bland, W. P. U.S. Patent 4,155,746, 1979.
256 (log
3
3.09), 298 (2.80), 380 (3.40), 387 (3.36); nmax/cmꢁ1
3. Wigand, R.; Guerra, J. M. J. Photochem. Photobiol., A: Chem. 1995, 88, 35e38.
4. Moody, C. J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, 1984; Vol. 3, pp 1039e1086.
5. Smalley, R. K. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 6, pp 695e735.
6. Geevers, J.; Trompen, W. P. Recl. Trav. Chim. Pays-Bas 1974, 93, 270e272.
7. Koutentis, P. A.; Rees, C. W.; White, A. J. P.; Williams, D. J. Chem. Commun. 2000,
303e304.
8. Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 2000, 1089e1094.
9. Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 2000, 1081e1088.
10. Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 2000, 2601e2607.
11. Kalogirou, A. S.; Koutentis, P. A.; Rikkou, M. D. Tetrahedron 2010, 66, 1817e1820.
12. Ioannidou, H. A.; Kizas, C.; Koutentis, P. A. Org. Lett. 2011, 13, 3466e3469.
13. Ioannidou, H. A.; Kizas, C.; Koutentis, P. A. Org. Lett. 2011, 13, 5886e5889.
14. Ioannidou, H. A.; Koutentis, P. A. Tetrahedron 2012, 68, 2590e2597.
15. Peake, C. J.; Harnish, W. N.; Davidson, B. L. U.S. Patent 4,100,281, 1978.
16. Peake, C. J.; Harnish, W. N.; Davidson, B. L. U.S. Patent 4,143,138, 1979.
17. Peake, C. J.; Harnish, W. N.; Davidson, B. L. U.S. Patent 4,201,780, 1980.
18. Portnoy, R. C. U.S. Patent 4,497,807, 1985.
3076w (Ar CH), 1622s (C]O), 1595m, 1514w, 1504w, 1454w, 1435m,
1408s, 1375s, 1352w, 1339m, 1263m, 1223w, 1211w, 1182w, 1080w,
1047m, 1032w, 1001m, 866m, 853w, 835w, 802w, 772w, 751m; dH
(500 MHz; CDCl3) 8.26 (1H, d, J 3.5, thienyl H), 8.19e8.17 (2H, m, Ph
H), 7.64 (1H, d, J 5.0, thienyl H), 7.50e7.48 (3H, m, Ph H), 7.19 (1H,
dd, J 4.5, 4.5, thienyl H); dC (125 MHz; CDCl3) 163.2 (s), 159.4 (s),
155.5 (s), 136.2 (s), 134.5 (s), 134.4 (d), 133.4 (d), 132.2 (d), 129.0 (d),
128.3 (d), 127.7 (d); m/z (EI) 272 (Mþ, 100%), 141 (79), 135 (86), 109
(18), 103 (17), 91 (6), 77 (20), 71 (8), 58 (7), 51 (7).
4.17. 3-(1-Methyl-1H-pyrrol-2-yl)-5-phenyl-4H-1,2,6-
thiadiazin-4-one (13f)
Similar treatment of 3-bromo-5-phenyl-4H-1,2,6-thiadiazin-4-
one (12b) (50.0 mg, 0.19 mmol) with 1-methyl-2-(tributyltin)pyr-
19. Flowerday, P.; Perkins, M. J. Tetrahedron Lett. 1968, 9, 1261e1264.
20. Flowerday, P.; Perkins, M. J.; Arthur, A. R. J. J. Chem. Soc. C 1970, 290e297.
21. Haddon, R. C.; Kaplan, M. L.; Marshall, J. H. J. Am. Chem. Soc. 1978, 100,
1235e1239.
role (70.3 mL, 0.19 mmol) gave the title compound 13f (44 mg, 86%)
as yellow plates, mp 182e184 ꢀC (from cyclohexane), Rf 0.49
(hexane/DCM, 1:1); (found: C, 62.37; H, 4.15; N, 15.55. C14H11N3OS
ꢀ
22. Gomez, T.; Macho, S.; Miguel, D.; Neo, A. G.; Rodríguez, T.; Torroba, T. Eur. J. Org.
requires C, 62.43; H, 4.12; N, 15.60%); lmax (DCM)/nm 252 (log
3.24), 380 (3.47), 385 inf (3.43); nmax/cmꢁ1 2957w, 1686w, 1626s
(C]O), 1597w, 1524m, 1489s, 1466w, 1416s, 1404m, 1368m, 1342w,
1315w, 1298s, 1269w, 1250w, 1236w, 1225w, 1184w, 1150w, 1096w,
1069s,1040w,1026m, 974w, 924w, 894w, 874w, 854w, 818w, 799w,
3
Chem. 2005, 5055e5058.
23. Macho, S.; Miguel, D.; Neo, A. G.; Rodríguez, T.; Torroba, T. Chem. Commun.
2005, 334e336.
24. Lanni, E. L.; Bosscher, M. A.; Ooms, B. D.; Shandro, C. A.; Ellsworth, B. A.; An-
derson, C. E. J. Org. Chem. 2008, 73, 6425e6428.
25. Harwood, L. M. Aldrichimica Acta 1985, 18, 25.