Pd-catalyzed C-N coupling of primary (het)arylamines with 5-substituted 3-chloro-4H-1,2,6-thiadiazin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2018.05.068

The Buchwald-Hartwig Pd-catalyzed C-N coupling reaction of 5-substituted 3-chloro-4H-1,2,6-thiadiazin-4-ones with primary (het)arylamines is described, affording twenty new 3,5-disubstituted 4H-1,2,6-thiadiazin-4-ones in 56–99% yield. The protocol enables

Full text of DOI:10.1016/j.tetlet.2018.05.068

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed C-N coupling of primary (het)arylamines with
5-substituted 3-chloro-4H-1,2,6-thiadiazin-4-ones
b
Andreas S. Kalogirou a,b, , Panayiotis A. Koutentis
⇑
a Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenis Str., Engomi, P. O. Box 22006, 1516 Nicosia, Cyprus
b Department of Chemistry, University of Cyprus, P. O. 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:
The Buchwald-Hartwig Pd-catalyzed C-N coupling reaction of 5-substituted 3-chloro-4H-1,2,6-thiadi-
azin-4-ones with primary (het)arylamines is described, affording twenty new 3,5-disubstituted 4H-
1,2,6-thiadiazin-4-ones in 56–99% yield. The protocol enables the mild preparation of difficult to access
3,5-dianilino-1,2,6-4H-thiadiazin-4-ones. The reaction scope and limitations are discussed.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 22 April 2018
Revised 18 May 2018
Accepted 23 May 2018
Available online xxxx
Keywords:
Buchwald coupling
Heterocycle
1,2,6-thiadiazines
C-N coupling
Superstable Pd(0)
Introduction
Non S-oxidized 4H-1,2,6-thiadiazines have been known for over
40 years. Selected 3-chloro-4H-1,2,6-thiadiazin-4-ones are plant
antifungals,1 while other derivatives have been studied as
‘‘extreme quinoids”,2 liquid crystals or near-infrared dyes.3 More
recently, 4H-1,2,6-thiadiazines were proposed as precursors to
radical anions for molecule-based magnetic and conducting mate-
rials,4 and small molecules containing 4H-1,2,6-thiadiazin-4-one
were studied as electron donors in solution-processed bulk hetero-
junction solar cells.5 In spite of these useful properties, work on
this heterocycle remains limited.
Most syntheses of non S-oxidized 4H-1,2,6-thiadiazines involve
either 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1) or 3,4,4,5-tetra-
chloro-1,2,6-thiadiazine (2), both of which can be readily prepared
from malononitrile and SCl2 (Scheme 1).6
As part of our ongoing studies into rare heterocycles, we have
expanded the synthetic scope of 3,5-dichlorothiadiazinone 1, by
systematically developing protocols for difficult to achieve chem-
istry such as various condensation reactions at the C4 carbonyl.7
Another difficult to achieve reaction is the double displacement
of the chlorides by anilines: the first chloride can be readily
Scheme 1. Chemistry of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1).
displaced by anilines using stoichiometric amounts of aniline
(2 equiv.) in EtOH, at ca. 0–20 °C.6 Nevertheless, owing to electron
release from the new anilino group, the electrophilicity of the new
3-anilino-5-chloro-1,2,6-4H-thiadiazin-4-one
3 is significantly
reduced. Consequently, the second displacement of the remaining
chloride by aniline requires forcing conditions: i.e. excess aniline in
the absence of solvent at ca. 150–180 °C. These conditions are
incompatible with sensitive functionality that cannot tolerate high
⇑
Corresponding author at: Department of Life Sciences, School of Sciences,
European University Cyprus, 6 Diogenis Str., Engomi, P. O. Box 22006, 1516 Nicosia,
Cyprus.
E-mail address: A.Kalogirou@external.euc.ac.cy (A.S. Kalogirou).
https://doi.org/10.1016/j.tetlet.2018.05.068
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kalogirou A.S., Koutentis P.A. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.05.068

2
A.S. Kalogirou, P.A. Koutentis / Tetrahedron Letters xxx (2018) xxx–xxx
temperatures, or expensive anilines that cannot be used in large
excess. As such, we investigated Pd-catalyzed Buchwald-Hartwig
coupling8 protocols to introduce the second aniline under milder
conditions to enable a more versatile method of preparing sym-
metric and asymmetric 3,5-dianilino-4H-1,2,6-thiadiazin-4-ones
4. While the use of Pd catalysts in the presence of a weakly aro-
matic dichlorothiadiazinone had initially been avoided over fears
that sulfur would poison the catalyst, studies have since revealed
the tolerance of the ring system to Pd-catalyzed Suzuki-Miyaura,9a
Stille9a,b and Sonogashira9a couplings.
were significantly slower (24 h) with the use of 4,5-bis
(diphenylphosphino)-9,9-dimethylxanthene (Xanthphos) (104.6°),
marginally faster (2 h) with the use of 1,4-bis(diphenylphos-
phino)butane (dppb) (97.0°) and significantly faster (0.5 h) with
bis[(2-diphenylphosphino)phenyl] ether (DPEPhos) (101.5°)
(Table 1, entries 3, 4 and 5, respectively) cf. BINAP (92.8°). The
use of DPEPhos not only shortened the reaction time but also led
to a near quantitative yield of 98%. It is noteworthy that the use
of bidentate ligands with large bite angles favors the coupling of
anilines with aryl halides by promoting the reductive elimination
step.12
While the latter conditions (Table 1, entry 5) worked well for
the Buchwald-Hartwig coupling of anilinothiadiazine 3a with ani-
line, a preliminary screen of other anilines revealed that the use of
electron rich 2-methoxy and 2-methylanilines failed to proceed to
completion (data not shown). Fortunately, replacing Pd(OAc)2 by
Pd{[3,5-(F3C)2C6H3]3P}3 [aka Superstable Pd(0)], also led to equally
fast and near quantitative reactions of aniline with 3-anilino-5-
chloro-1,2,6-thiadiazine 3a (Table 1, entry 6) and under these
new conditions the reactions with electron rich anilines worked
well (Table 2, entries 2 and 7).
Nevertheless, while Superstable Pd(0) worked well with DPE-
Phos as the ligand (Table 1, entry 6), the analogous reaction with
Xantphos as the ligand was significantly slower (20 h) and gave
product 4a in lower yield (72%) (Table 1, entry 7). Interestingly,
the use of Superstable Pd(0) to support C-N coupling chemistry is
not common, but we have successfully used this catalyst for the
Buchwald-Hartwig coupling of (het)arylamines with 5,50-
dibromo-2,20-bithiazoles.13 Repeating the reaction of anilinothiadi-
azine 3a and aniline using the optimized reaction conditions but in
the absence of a Pd catalyst (Table 1, entry 8) led to no reaction
supporting the need for Pd-catalysis. It is also worthy to note that
in the absence of a bidentate ligand the reaction failed to proceed
to completion within 24 h (Table 1, entry 9).
Results and discussion
Treatment of dichlorothiadiazinone 1 with aniline (2 equiv.) in
EtOH at ca. 20 °C for 1 h gave 3-chloro-5-(phenyl-amino)-4H-
1,2,6-thiadiazin-4-one (3a) in 95% yield via a chromatography free
literature procedure.6 Anilinothiadiazine 3a was subsequently
used as the starting point for identifying suitable Buchwald-Hart-
wig reaction conditions for the preparation of 3,5-bis(pheny-
lamino)-4H-1,2,6-thiadiazin-4-one (4a). Initially, we confirmed
the known preparation of bisanilinothiadiazine 4a by treating
anilinothiadiazine 3a with neat aniline (8 equiv.) at ca. 180 °C,
which in our hands was complete in 45 min and gave the desired
product 4a in 84% yield.6 The reaction temperature can be lowered
to ca. 150 °C to give the product in a similar 83% yield; however at
ca. 100 °C or when EtOH was used as a solvent at ca. 78 °C, no reac-
tion occurred.
The search for suitable Buchwald-Hartwig reaction conditions
focused on the reaction of anilines with 2-chloropyridines,10 which
are somewhat similar to chlorothiadiazines in that they are both
electron deficient hetarenes bearing chlorine groups. As such,
treatment of anilinothiadiazine with aniline (1.2 equiv.), using Pd
(OAc)2 (4 mol%), [2,20-bis(diphenylphosphino)-1,10-binaphthyl]
(BINAP) (4 mol%) and powdered Cs2CO3 (3 equiv.), in anhydrous
PhMe at ca. 110 °C for 1.5 h under an argon atmosphere, gratify-
ingly gave the desired dianilinothiadiazine 4a in 63% yield (Table 1,
entry 1). By changing both the solvent and base to anhydrous 1,4-
dioxane and powdered K2CO3 (2.4 equiv.), respectively, the catalyst
loading and reaction temperature could be lowered to 1.25 mol%
and ꢀ102 °C, respectively, and the product yield improved to 88%
(Table 1, entry 2). A subsequent bidentate ligand screen to investi-
gate the influence of bite angle11 revealed that the reaction times
Under the optimized Buchwald-Hartwig coupling conditions:
Superstable Pd(0) (1.25 mol%), DPEPhos (5 mol%), K2CO3 (2.4
equiv.), anhydrous 1,4-dioxane, 102 °C, under an argon atmo-
sphere, we systematically examined the scope of this (het)arylam-
ination protocol (Table 2). ortho-Substituted anilines were selected
to illustrate the effect of both steric and electronic effects. In most
cases, the reaction of 3-anilino-5-chloro-1,2,6-thiadiazinone 3a
with primary anilines bearing either electron donating (Table 2,
Table 1
Reaction of 3-chloro-5-(phenylamino)-4H-1,2,6-thiadiazin-4-one (3a) with aniline (1.2 equiv.) under an argon atmosphere.
Entry
Solvent
Catalyst (mol%)
Ligand (mol%)
Base (equiv.)
Temp. (°C)
Time (h)
Yield 4a (%)a
1
2
3
4
5
6
7
8
9
PhMe
Pd(OAc)2 (4)
BINAP (4)
BINAP (5)
Xanthphos (5)
dppb (5)
DPEPhos (5)
DPEPhos (5)
Xanthphos (5)
DPEPhos (5)
–
Cs2CO3 (3)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
110
102
102
102
102
102
102
102
102
1.5
4
24
2
0.5
0.5
20
24
24
63
88
92
90
98
99
72
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Pd(OAc)2 (1.25)
Pd(OAc)2 (1.25)
Pd(OAc)2 (1.25)
Pd(OAc)2 (1.25)
Superstable Pd(0) (1.25)
Superstable Pd(0) (1.25)
–
b
–
c
Superstable Pd(0) (1.25)
–
a
b
c
Isolated yields.
No reaction.
Incomplete reaction.
Please cite this article in press as: Kalogirou A.S., Koutentis P.A. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.05.068

A.S. Kalogirou, P.A. Koutentis / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 2
Reaction of 5-subsituted 3-chloro-4H-1,2,6-thiadiazin-4-ones 3 with (het)arylamines (1.2 equiv.), in dry 1,4-dioxane, with DPEPhos (5 mol%), K2CO3 (2.4 equiv.) and Superstable
Pd(0) (1.25 mol%) at ca. 102 °C, under an argon atmosphere.
Entry
3a–e (R1)
R2
R3
Time (h)
Yield 4a–z (%)a
1
2
3
4
5
6
7
8
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3a (PhNH)
3b (PhS)
Ph
2-Tol
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
–
0.5
2
8
1
1
4
2
4
1
3
2
1.5
18
1
4a (99)
4b (61)
4c (85)b
4d (81)
4e (90)
4f (68)
4 g (89)
4 h (83)
4i (86)b
4j (82)
2-AcC6H4
2-NCC6H4
2-HO2CC6H4
2-F3CC6H4
2-MeOC6H4
2-HOC6H4
2-O2NC6H4
2-ClC6H4
2-BrC6H4
4-BrC6H4
2-IC6H4
Pyrid-2-yl
Pyrid-4-yl
Pyrimid-2-yl
1,2,4-triazin-3-yl
Thiaz-2-yl
Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4k (91)b
4L (92)
4m (ꢁ)c
4n (70)b
4o (72)
4p (78)
4q (85)
4r (91)
4s (ꢁ)d
4t (ꢁ)d
4u (ꢁ)d
4v (96)
4w (93)
4x (56)
4y (ꢁ)e
1
0.5
0.5
0.5
24
18
18
1
1
2
2
Ph
Carbazol-1-yl
Ph
Ph
Ph
Ph
H
H
H
H
3c (PhO)
3d (morpholino)
3e (NH2)
a
b
c
Isolated yields.
Product was unstable to chromatography, chromatography free isolation applied.
Complex reaction mixture (by TLC).
No reaction.
d
e
Intractable baseline (by TLC).
entries 2, 8, 9) or electron withdrawing (Table 2, entries 5, 6, 7, 10,
11) ortho-substituents worked well to provide the desired dianilino
products in high yield (Table 2, entries 1–14). A range of useful
functionality was tolerated including cyano (Table 2, entry 4), car-
boxylic acid (Table 2, entry 5), hydroxyl (Table 2, entry 8) and
chloro groups (Table 2, entry 10). Interestingly, there were three
dianilinothiadiazines that showed instability to chromatography
(verified by 2D TLC) and had to be isolated using a non-chromato-
graphic workup, the derivatives of 2-acetoxy-, 2-nitro and 2-bro-
moanilines (Table 2, entries 3, 9 and 11, respectively). The
reaction of 2-iodoaniline, unlike 2-bromoaniline, gave a complex
reaction mixture from which we were unable to isolate a major
product (Table 2, entry 13). Interestingly, we also examined the
reaction of the analogous 4-bromoaniline and observed that the
product 4-bromoanilinothiadiazine 4l was stable to chromatogra-
phy and was isolated in 92% yield (Table 2, entry 12). More steri-
cally hindered secondary anilines such as N-methylaniline,
diphenylamine (Table 2, entries 19 and 20) or the use of carbazole
(Table 2, entry 21) failed to react under the reaction conditions and
3-anilino-5-chlorothiadiazine 3a was fully recovered.
chromatography similar to the 2-acetoxy, 2-nitro and 2-bromo
derivatives and required a non-chromatographic workup (Table 2,
entries 14).
The Buchwald-Hartwig-mediated coupling of 5-phenylthio-, 5-
phenoxy-, and 5-morpholino-substituted 3-chlorothiadiazines 3b–
d with aniline also worked (Table 2, entries 22–24) to give the
respective phenylthiol and phenoxy analogues 4v (96%) and 4w
(93%) in excellent yields while 3-anilino-5-morpholinothiadiazine
4x was formed in only a moderate 56% yield (Table 2, entry 25).
Finally, efforts to couple aniline to 3-amino-5-chloro-1,2,6-thiadi-
azin-4-one 3e led to complete consumption of the starting thiadi-
azine and an intractable polar baseline (by TLC).
Conclusion
A Buchwald-Hartwig C-N coupling protocol for the (het)arylam-
ination of 3-chloro-4H-1,2,6-thiadiazin-4-ones was developed
which makes use of Superstable Pd(0) as the catalyst and DPEPhos
as the bidentate ligand. The protocol provides a mild alternative to
the nucleophilic displacement of the chloride of 3-chloro-4H-1,2,6-
thiadiazin-4-ones and importantly enables the rapid preparation of
difficult to access 3,5-di[(het)arylamino]thiadiazines in high yield.
The protocol tolerates use of primary anilines bearing steric, elec-
tron donating or withdrawing substituents, as well as electron rich
or poor hetarylamines. 2-Iodoaniline or secondary arylamines such
Furthermore, in most cases the Buchwald-Hartwig coupling of
3-anilino-5-chlorothiadiazine 3a with primary hetarylamines
(e.g., pyrid-4-yl-, pyramid-2-yl-, 1,2,4-triazin-2-yl-, thiaz-2-ylami-
nes) worked well to give the desired products in medium to high
yields with short reaction times (Table 2, entries 15–18). Interest-
ingly, 5-(pyrid-2-ylamino)thiadiazine 4n showed instability to
Please cite this article in press as: Kalogirou A.S., Koutentis P.A. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.05.068

4
A.S. Kalogirou, P.A. Koutentis / Tetrahedron Letters xxx (2018) xxx–xxx
as diphenylamine, carbazole or N-methylaniline are not tolerated.
The method can be used for the synthesis of 3,5-diaminoth-
iadizines containing sensitive or expensive arylamines.
References
1. (a) Peake CJ, Harnish WN, Davidson BL. U.S. Pat. 4,097,594, 1978;
(b) Peake CJ, Harnish WN, Davidson BL. U.S. Pat. 4,100,281, 1978;
(c) Peake CJ, Harnish WN, Davidson BL. U.S. Pat. 4,143,138, 1979;
(d) Peake CJ, Harnish WN, Davidson BL. U.S. Pat. 4,201,780, 1980;
(e) Portnoy RC. U.S. Pat. 4,497,807, 1985;
Acknowledgments
2. Haddon RC, Kaplan ML, Marshall JH. J Am Chem Soc. 1978;100:1235.
3. (a) Gómez T, Macho S, Miguel D, Neo AG, Rodríguez T, Torroba T. Eur J Org Chem.
2005;5055;
The authors thank the Cyprus Research Promotion Foundation
(Grants:
RΤΡAΤΗII/0308/06, NEKYP/0308/02 YCEIA/0506/19 and
(b) Macho S, Miguel D, Neo AG, Rodríguez T, Torroba T. Chem Commun.
2005;334.
ΕΝI X/0308/83) and the following organizations and companies
R
in Cyprus for generous donations of chemicals and glassware: the
State General Laboratory, the Agricultural Research Institute, the
Ministry of Agriculture, MedoChemie Ltd, Medisell Ltd and
Biotronics Ltd. Furthermore, we thank I. J. Stavrou and C. P. Kap-
nissi-Christodoulou for ESI-APCI+ mass spectra and the A. G. Leven-
tis Foundation for helping to establish the NMR facility at the
University of Cyprus.
4. Lonchakov AV, Rakitin OA, Gritsan NP, Zibarev AV. Molecules. 2013;18:9850.
5. Hermerschmidt F, Kalogirou AS, Min J, et al. J Mater Chem C. 2015;3:2358.
6. Geevers J, Trompen WP. Recl Trav Chim Pays-Bas. 1974;93:270.
7. (a) Kalogirou AS, Koutentis PA. Tetrahedron. 2014;70:8334;
(b) Ioannidou HA, Koutentis PA. Tetrahedron. 2012;68:2590.
8. Heravi MM, Kheilkordi Z, Zadsirjan V, Heydari M, Malmir M. J Organomet Chem.
2018;861:17.
9. (a) Ioannidou HA, Kizas C, Koutentis PA. Org Lett. 2011;13:3466;
(b) Ioannidou HA, Kizas C, Koutentis PA. Org Lett. 2011;13:5886.
10. Masters K-S, Rauws TRM, Yadav AK, Herrebout WA, Van der Veken B, Maes
BUW. Chem -Eur J. 2011;17:6315.
A. Supplementary data
11. Dierkes P, van Leeuwen PWNM. J Chem Soc Dalton Trans. 1999;1519.
12. van Leeuwen PWNM, Kamer PCJ, Reek JNH, Dierkes P. Chem Rev.
2000;100:2741.
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.05.068.
13. Koyioni M, Koutentis PA. Org Lett. 2017;19:174.
Please cite this article in press as: Kalogirou A.S., Koutentis P.A. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.05.068