Palladium catalyzed C-C coupling reactions of 3,5-dichloro-4 H -1,2,6-thiadiazin-4-one

Article abstract of DOI:10.1021/ol201212b

Palladium catalyzed Suzuki-Miyaura, Stille, and Sonogashira coupling reactions are reported for the electron-deficient heterocyclic scaffold 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1). Furthermore, 3,5-di(thien-2-yl)-4H- 1,2,6-thiadiazin-4-one (7m) is fur

Full text of DOI:10.1021/ol201212b

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3466–3469
Palladium Catalyzed CꢀC
Coupling Reactions of
3,5-Dichloro-4H-1,2,6-thiadiazin-4-one
Heraklidia A. Ioannidou, Christos Kizas, and Panayiotis A. Koutentis*
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
koutenti@ucy.ac.cy
Received May 6, 2011
ABSTRACT
Palladium catalyzed SuzukiꢀMiyaura, Stille, and Sonogashira coupling reactions are reported for the electron-deficient heterocyclic scaffold
3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1). Furthermore, 3,5-di(thien-2-yl)-4H-1,2,6-thiadiazin-4-one (7m) is further elaborated to afford the
tetrathienyl 3,5-bis[(2,20-bithien)-5-yl]-4H-1,2,6-thiadiazin-4-one (9). All compounds are fully characterized.
Various oxidized 1,2,6-thiadiazines such as the sulfoxides
and, more importantly, the sulfones have received consid-
erable attention in various areas of applied chemistry
Scheme 1. Synthesis of 4H-1,2,6-Thiadiazines 1 and 2
including the pharmaceutical,1 agrochemical,2 and materials3
sectors. Commercially, an important 1,2,6-thiadiazine is
bentazone [3-isopropyl-lH-2,l,3-benzothiadiazin-4(3H)-one
2,2-dioxide], which is a selective herbicide of long-standing.4
Surprisingly little, however, has appeared in the litera-
ture on nonoxidized 4H-1,2,6-thiadiazines. Monocyclic
3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1)5 and its 4-di-
cyanomethylene analogue 2-(3,5-dichloro-4H-1,2,6-thia-
diazin-4-ylidene)malononitrile (2)6 have been prepared,
the former in two steps starting from dichloromalononi-
trile and the latter in one step from tetracyanoethylene
(TCNE) (Scheme 1). Both are useful precursors to several
polycyclic 1,2,6-thiadiazine systems.7
Many monochloro derivatives of thiadiazinones have high
fungicidal activity,8 while fused 4H-1,2,6-thiadiazines such
(1) Breining, T.; Cimpoia, A. R.; Mansour, T. S.; Cammack, N.;
Hopewell, P.; Ashman, C. Heterocycles 1995, 41, 87.
(2) McKendry, L. H.; Bland, W. P. U.S. Patent 4,155,746, 1979.
(3) Wigand, R.; Guerra, J. M. J. Photochem. Photobiol., A: Chem.
as acenaphtho[5,6-cd][1,2,6]thiadiazine (3)9 and naphtho-
[1,8-cd:4,5-c0d0]bis([1,2,6]thiadiazine) (4)10 (Figure 1) have
been studied as examples of “extreme quinoids” that have
ambiguous aromatic character.
1995, 88, 35.
(4) Hamprecht, G.; Konig, K.-H.; Stubenrauch, G. Angew. Chem.,
€
Int. Ed. 1981, 20, 151.
(5) Geevers, J.; Trompen, W. P. Recl. Trav. Chim. Pays-Bas 1974, 93,
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(8) Peake, C. J.; Harnish W. N.; Davidson, B. L. U.S. Patent
4,097,594, 1978.
(9) (a) Flowerday, P.; Perkins, M. J. Tetrahedron 1968, 9, 1261. (b)
Flowerday, P.; Perkins, M. J.; Arthur, A. R. J. J. Chem. Soc. C 1970, 290.
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(6) (a) Koutentis, P. A.; Rees, C. W.; White, A. J. P.; Williams, D. J.
Chem. Commun. 2000, 303. (b) Koutentis, P. A.; Rees, C. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1089.
(7) (a) Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1
2000, 2601. (b) Kalogirou, A. S.; Koutentis, P. A.; Rikkou, M. D.
Tetrahedron 2010, 66, 1817.
r
10.1021/ol201212b
Published on Web 06/07/2011
2011 American Chemical Society

More recently, Torroba et al. prepared cyclopenta[1,2,6]-
thiadiazines 5 and 6 starting from cyclic enaminonitriles,11
some of which displayed unusual liquid crystalline proper-
ties or behaved as near-infrared dyes. The synthesis and
chemistry of 1,2,6-thiadiazines have been reviewed.12
Palladium-catalyzed CꢀC coupling reactions have
widely been used for the synthesis of alkylated and/or
arylated arenes and heteroarenes.15 Interestingly, while
there are many electron-rich symmetrical dihalo heterocyclic
systems that participate in palladium-catalyzed CꢀC cou-
pling reactions to give in one-pot bis-arylated/alkylated
systems there are relatively few examples of electron-poor
symmetrical dihaloheteroarenes, e.g., 1,2,5-thiadiazoles,16
1,3,4-thiadiazoles,17 pyridines,18 and pyrimidines.19
Owing to the facile displacement of chloride by a wide
variety of nucleophiles, the initial attempts at Suzukiꢀ
Miyaura coupling of the dichlorothiadiazinone 1 focused
on protocols that were nonaqueous with the hope of limit-
ing base-catalyzed hydrolysis of the heterocycle. Similar
anhydrous protocols worked well for the C-5 selective
SuzukiꢀMiyaura reactions of highly reactive 3,5-dichlor-
oisothiazole-4-carbonitrile.20 Nevertheless, when the dichlo-
rothiadiazinone 1 was reacted with phenylboronic acid
(2.2 equiv) and Pd(OAc)2 (5 mol %) in organic solvents
(PhH, PhMe, DCM, MeCN, 1,4-dioxane, THF) and
inorganic bases [M2CO3 (M = Li, Na, K, Cs), KHCO3,
KF, KOH, K3PO4] or organic (Et3N, i-Pr2NEt, pyridine)
together with phase-transfer agents (18-C-6, Adogen 464,
Aliquat 336, BnEt3NI, BnEt3NCl,) only mixtures of un-
reacted dichlorothiadiazinone 1 and mono- and bispheny-
lated thiadiazines were isolated after 24 h. In light of this,
we switched to biphasic systems, and fortunately, this led
to complete consumption of the dichlorothiadiazinone 1.
We screened a range of solvents (PhH, PhMe, DCM,
1,4-dioxane, DME, MeCN, THF, DMA, DMF,), bases
[KOH, M2CO3, MHCO3, MF (M = Na, K, Cs)], and
catalysts [(Pd(Ph3P)4, Pd(OAc)2, (Ph3P)2PdCl2, (PhCN)2-
PdCl2, (MeCN)2PdCl2, (dba)3Pd2, [1,10-(Ph2P)ferrocene]-
PdCl2.DCM)]. The best conditions required the use of
PhB(OH)2 (2.2ꢀ3 equiv), Pd(Ph3P)4 (5mol%),andNa2CO3
(2 equiv) in either 1,4-dioxane/H2O (5:3) or benzene/H2O
(5:3) at 20ꢀ100 °C. The concentration of the reaction
mixture proved to be important: high concentrations
(e.g., 0.8 mL for 0.27 mmol of 1) led to faster and cleaner
reaction. Using the best conditions, 12 analogues were
synthesized that tested both steric and electronic limits
(Table 1).
Figure 1. Selected fused 4H-1,2,6-thiadiazines.
The known chemistry of dichlorothiadiazines 1 and 2
includes nucleophilic substitution of the C-3 and/or C-5
chlorine atoms by nitrogen, oxygen, and sulfur nucleo-
philes.7,8 X-ray diffraction shows the thiadiazine ring of
thiadiazinone 1 to be almost planar13 while that of the
ylidenemalononitrile 2 to be a shallow boat.6a Bird’s
aromaticity index (IA), based upon the statistical evalua-
tion of deviations in peripheral bond orders derived from
experimental bond lengths,14 gives IA 5414 and 606a for
thiadiazines 1 and 2, respectively, that indicated modest
aromaticity (cf. IA = 53 for furan and 100 for benzene).
Owing to these properties, we were interested in incorporating
the 4H-1,2,6-thiadiazine motif into π-conjugated polymers
(Figure 2). As such, we needed to develop efficient conditions
for C-functionalization of the C-3 and C-5 positions.
Figure 2. Proposed 4H-1,2,6-thiadiazine polymers.
In most cases, 2-substituted phenylboronic acids reacted
as well as the 3- and 4-substituted analogues, indicating
that there was little steric effect; however, when the more
sterically demanding 2,6-dimethylphenylboronic acid was
usedno productwas obtained(Table1, entry 5). Inthe case
of 3-nitrophenyl analogue, the yield was low and could not
Herein, we describe several SuzukiꢀMiyaura, Stille, and
Sonogashira palladium-catalyzed CꢀC coupling reactions
of dichlorothiadiazinone 1 to give symmetrical 3,5-bis-
arylated, heteroarylated, and alkynylated thiadiazinones.
(16) Merschaert, A.; Gorissen, H. J. Heterocycles 2003, 60, 29.
(17) Yasuda, T.; Imase, T.; Nakamura, Y.; Yamamoto, T. Macro-
molecules 2005, 38, 4687.
(18) (a) Leblond, J.; Gao, H.; Petitjean, A.; Leroux, J.-C. J. Am.
Chem. Soc. 2010, 132, 8544. (b) Tobe, Y.; Nakanishi, H.; Sonoda, M.;
Wakabayashi, T.; Achiba, Y. Chem. Commun. 1999, 1625. (c) Abe, H.;
Machiguchi, H.; Matsumoto, S.; Inouye, M. J. Org. Chem. 2008, 73,
4650. (d) Heller, M; Schubert, U. S. J. Org. Chem. 2002, 67, 8269.
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(11) (a) Gomez, T.; Macho, S.; Miguel, D.; Neo, A. G.; Rodrı
T.; Torroba, T. Eur. J. Org. Chem. 2005, 5055. (b) Macho, S.; Miguel,
D.; Neo, A. G.; Rodrıguez, T.; Torroba, T. Chem. Commun. 2005, 334.
´
guez,
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(12) Weintraub, P. M. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Turnbull,
K., Eds.; Elsevier: Oxford, 2008; Vol. 9, Chapter 9.07, p 3355.
(13) Harkema, S. Acta Crystallogr., Sect. B 1978, 34, 2927.
(14) (a) Bird, C. W. Tetrahedron 1986, 42, 89. (b) Bird, C. W.
Tetrahedron 1992, 48, 335.
~
(19) (a) Moreno-Manas, M.; Pleixats, R.; Serra-Muns, A. Synlett
ꢀ
2006, 3001. (b) Darabantu, M.; Boully, M.; Turck, A.; Ple, N. Tetra-
hedron 2005, 61, 2897.
(20) Christoforou, I. C.; Koutentis, P. A.; Rees, C. W. Org. Biomol.
Chem. 2003, 1, 2900.
(15) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64,
3047. (b) Yin, L; Liebscher, J. Chem. Rev. 2007, 107, 133. (c) Espinet, P.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704.
Org. Lett., Vol. 13, No. 13, 2011
3467

Table 1. Reaction of Dichlorothiadiazinone 1 (0.273 mmol) with
RB(OH)2 (2.2 equiv), Pd(Ph3P)4 (5 mol %), and Na2CO3 (2
equiv) in Dioxane/H2O (0.5:0.3 mL) at 20ꢀ100 °C
Table 2. Reaction of Dichlorothiadiazinone 1 (0.273 mmol) with
RSnBu3, (Ph3P)2PdCl2 (5 mol %) in MeCN (1 mL) at 20ꢀ82 °C
entry
R
RSnBu3 (equiv) time (h) yield (%)
entry
RB(OH)2 (equiv)
PhB(OH)2 (2.2)
time (min)
yield (%)
1
2
3
4
5
6
7
8
Ph
2.2
2.2
2.2
2.2
2.2
2.2
3
2.5
0.75
1
7a (95)
7n (92)
7m (92)
7o (93)
1
2
20
30
30
15
40
15
15
15
40
40
40
30
30
30
15
75
60
60
60
30
7a (91)
7b (94)
7c (91)
fur-2-yl
2-TolB(OH)2 (2.2)
thien-2-yl
N-Me-pyrrol-2-yl
thiazol-2-yl
vinyl
3
3-TolB(OH)2 (2.2)
1
a
4
4-TolB(OH)2 (2.2)
7d (99)
a
20
a
b
b
5
2,6-Me2C6H3B(OH)2 (2.2)
2-MeOC6H4B(OH)2 (2.2)
3-MeOC6H4B(OH)2 (2.2)
4-MeOC6H4B(OH)2 (2.2)
2-ClC6H4B(OH)2 (2.2)
3-ClC6H4B(OH)2 (2.2)
4-ClC6H4B(OH)2 (2.2)
3-O2NC6H4B(OH)2 (2.2)
3-O2NC6H4B(OH)2 (3)
3-O2NC6H4B(OH)2 (4)
thien-3-ylB(OH)2 (2.2)
thien-2-ylB(OH)2 (2.2)
thien-2-ylB(OH)2 (3)
pyrid-3-ylB(OH)2 (2.2)
pyrid-4-ylB(OH)2 (2.2)
MeB(OH)2 (2.2)
4
4
6
7e (87)
7f (88)
7g (86)
7h (80)
7i (81)
7j (89)
7k (54)
7k (64)
7k (66)
71 (98)
7m (42)
propynyl
Bu3Sn
7
3
24
8
a Consumption of the starting material, no product. b Recovered
starting material.
9
10
11
12
13
14
15
16
17
18
19
20
of our ongoing goal for the incorporation of thiadiazine
into conjugated polymers, we proceeded to synthesize
oligothiophene 1,2,6-thiadiazin-4-one 9 (Scheme 2). Oligo-
and polythiophenes are shown to be important as ad-
vanced electronic and photonic materials, such as organic
TFT’s, liquid crystals, photovoltaic cells, etc.22
7m (90)
a
a
a
a Consumption of the starting material, no product.
Scheme 2. Synthesis of Tetrathienyl-1,2,6-thiadiazine 9
be significantly improved by increasing the quantity of the
boronic acid from 2.2 to 4 equiv (entries 12ꢀ14). The other
electron-poor 3- and 4-pyridylboronic acids gave only
intractable polar products (baseline on TLC) (entries 18
and 19). The reaction with methylboronic acid was also
unsuccessful (entry 20). Fortunately, both the 2- and
3-thienylboronic acids reacted to give the expected bisthienyl-
substituted thiadiazinones 7m and 7l, although the former
required additional equivalents to give high yields (entry 17).
This was not suprising considering the ease with which
thien-2-ylboronic acid suffers protodeboronation.21
The Stille coupling of dichlorothiadiazinone 1 with phenyl,
fur-2-yl, thien-2-yl, and N-methylpyrrol-2-yltributylsta-
nnanes in the presence of (Ph3P)2PdCl2 (5 mol %) in MeCN
gave the expected products in very high yields. Other
stannyl reagents such as thiazol-2-yl, vinyl, propynyl,
and tributylstannyl led to either decomposition or no
reaction (Table 2).
Bromination of bis(thien-2-yl) 1,2,6-thiadiazin-4-one
7m using 2 equiv of either Br2 or NBS in AcOH at low
temperature (13ꢀ15 °C) gave the 3,5-di(5-bromothien-2-yl)-
4H-1,2,6-thiadiazin-4-one (8) in 80% yield. The latter under-
went the Stille conditions developed previously using
2-tributylstannylthiophene in refluxing MeCN to afford
the tetrathiophene 9 in very high yield (95%).
Having access to a high-yielding synthesis of 3,5-di-
(thien-2-yl)-4H-1,2,6-thiadiazin-4-one (7m) and in light
(22) (a) Briehn, C. A.; Schiedel, M.-S.; Bonsen, E. M.; Schuhmann,
€
Chem. Rev. 1996, 96, 537. (c) Facchetti, A.; Yoon, M.-H.; Stern, C. L.;
Katz, H. E.; Marks, T. J. Angew. Chem., Int. Ed. 2003, 42, 3900.
(d) Izumi, T.; Kobashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. J. Am.
Chem. Soc. 2003, 125, 5286.
(21) (a) Brown, R. D.; Buchanan, A. S.; Humffray, A. A. Aust. J.
Chem. 1965, 18, 1521. (b) Roques, B. P.; Florentin, D.; Callanquin, M.
J. Heterocycl. Chem. 1975, 12, 195. (c) Florentin, D.; Fournie-Zaluski,
M. C.; Callanquin, M.; Roques, B. P. J. Heterocycl. Chem. 1976
13, 1265.
W.; Bauerle, P. Angew. Chem., Int. Ed. 2001, 40, 4680. (b) Tour, J. M.
ꢀ
3468
Org. Lett., Vol. 13, No. 13, 2011

(4 equiv), (Ph3P)2PdCl2 (5 mol %), and CuI (10 mol %)
at rt (Table 3, entry 1). Using these conditions, the 3,5-
bis(thien-3-ylacetylene) derivative 11b was synthesized
in 69% yield at 20ꢀ80 °C. While 3-pyridinylacetylene
gave the 3,5-bis(pyrid-3-ylacetylene) 11c in 68% yield,
the 2-pyridinyl acetylene led to a very complex reaction
mixture even at higher temperature (80 °C). Use of the
ferrocenyl acetylene (3 equiv) gave mixtures of the mono-
and disubstituted thadiazin-4-ones 10 and 11d in 10 and
17% yields, respectively, while use of TMS-acetylene led
to decomposition of the starting material (Table 3).
In conclusion, the dichlorothiadiazinone 1 undergoes
Pd-catalyzed SuzukiꢀMiyaura, Stille, and Sonogashira
CꢀC coupling reactions to afford symmetrical bis-
arylated, heteroarylated, and alkynylated systems, respec-
tively. 3,5-Di(thien-2-yl)-4H-1,2,6-thiadiazin-4-one (7m)
was further modified to afford 3,5-bis[(2,20-bithien)-5-yl]-
4H-1,2,6-thiadiazin-4-one (9).
Table 3. Reaction of Dichlorothiadiazinone 1 (0.273 mmol) with
Acetylene (2.2 equiv), Et3N (4 equiv), CuI (10 mol %), and
(Ph3P)2PdCl2 (5 mol %) in MeCN
entry
R
time (min)
yield (%)
11a (73)
1
2
3
4
5
6
Ph
10
30
thien-3-yl
pyrid-2-yl
pyrid-3-yl
ferrocenyl
TMS
11b (69)
a
30
45
11c (68)
180
60
10 (10), 11d (17)
b
a Complex reaction mixture. b Decomposition.
Acknowledgment. We thank the Cyprus Research Pro-
motion Foundation (GrantNo. ΠENEK, ENIΣX/0504/
08), the State General Laboratory, the Agricultural Re-
search Institute, the Ministry of Agriculture, and Biotro-
nics Ltd. for generous donations of glassware and
chemicals. We also thank the A. G. Leventis Foundation
for helping to establish the NMR facility at the University
of Cyprus.
The photophysical properties of the bis- and tetrathio-
phenes 7m and 9 are now under investigation.
Attempts to carry out the Sonogashira reaction between
the dichlorothiadiazinone 1 and phenylacetylene included
the examination of the solvent (PhH, PhMe, 1,4-dioxane,
THF, DMF, DCM, MeCN) and organic base (Et3N,
€
Hunig’s, lutidine, pyridine) using 5 mol % of a palladium
source [Pd(Ph3P)4, (dba)3Pd2, Pd(OAc)2, (PhCN)2PdCl2,
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(MeCN)2PdCl2, (Ph3P)2PdCl2, and[1,10-(Ph2P)ferrocene]ꢀ
PdCl2 DCM)] and CuI (10 mol %) at rt. The best yield of
bisacetylene 11a (73%) was obtained using MeCN, Et3N
3
Org. Lett., Vol. 13, No. 13, 2011
3469