Synthesis of N-Aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines from 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine

Article abstract of DOI:10.1021/acs.orglett.5b02237

Condensation of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine with a range of anilines gave 22 N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines in 43-96% yields. The scope and limitations of this condensation are briefly investigated. Furthermore, mono- and bis-substitution of the C-3 and C-5 chlorines of 3,5-dichloro-N-phenyl-4H-1,2,6-thiadiazin-4-imine by amine and alkoxide nucleophiles is explored. Finally, Stille coupling chemistry is used to prepare several N-phenyl-3,5-diaryl-4H-1,2,6-thiadiazin-4-imines.

Full text of DOI:10.1021/acs.orglett.5b02237

Letter
pubs.acs.org/OrgLett
Synthesis of N‑Aryl-3,5-dichloro‑4H‑1,2,6-thiadiazin-4-imines from
3,4,4,5-Tetrachloro‑4H‑1,2,6-thiadiazine
Andreas S. Kalogirou, Maria Manoli, and Panayiotis A. Koutentis*
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
S
* Supporting Information
ABSTRACT: Condensation of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine
with a range of anilines gave 22 N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-
imines in 43−96% yields. The scope and limitations of this condensation
are briefly investigated. Furthermore, mono- and bis-substitution of the C-3
and C-5 chlorines of 3,5-dichloro-N-phenyl-4H-1,2,6-thiadiazin-4-imine by
amine and alkoxide nucleophiles is explored. Finally, Stille coupling
chemistry is used to prepare several N-phenyl-3,5-diaryl-4H-1,2,6-thiadiazin-4-imines.
Scheme 1. Synthesis of 3,5-Diaryl-1,2,6-thiadiazin-4-ones 3
and Dicyanoylidines 4
he majority of research on 1,2,6-thiadiazines has focused
Ton the S-oxidized analogues. Nonoxidized 4H-1,2,6-
thiadiazines are less well studied. Despite this, several analogues
display interesting biological and physical properties: 5-
substituted 3-chloro-4H-1,2,6-thiadiazin-4-ones act as fungi-
cides,1 while some fused 4H-1,2,6-thiadiazines behave as
“extreme quinoids”,2 as atypical liquid crystals, or as near-
infrared dyes.3 More recently, non-S-oxidized 4H-1,2,6-
thiadiazines were proposed as precursors to molecule-based
radical anions,4 as monomers of conjugated polymers,5,6 and as
acceptor components in small molecule donor−acceptor−
donor containing solution-processed bulk heterojunction solar
cells.7−9
To date, the most used non-S-oxidized 4H-1,2,6-thiadiazine
scaffold is 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1). The C-3/
5 chlorine atoms readily undergo nucleophilic substitution by
N-, O-, and S-nucleophiles10 and can participate in palladium
catalyzed Stille, Suzuki−Miyaura, and Sonogashira couplings.11
Furthermore, reactions with vicinal bisnucleophiles afford
highly colored polycyclic systems.6c
thionation followed by reaction with tetracyanoethylene oxide
(TCNEO)11 (Scheme 1).
While the C-3 and C-5 positions of thiadiazinone 1 can be
easily manipulated, it has, to date, been difficult to develop
reactions to modify the C-4 position which bears an attractive
carbonyl moiety. Simple condensation reactions fail because of
three competing reactions: (1) direct nucleophilic displacement
of the C-3/5 chlorine atoms; (2) thiophilic attack that leads to
ring cleavage owing to the relatively weak S−N bond and the
good nucleofugality of the C-3/5 chlorine atoms; and (3)
halophilic attack that also leads to cleavage of the ring system
via the weak N−S bond and concomitant formation of a
thermodynamically stable nitrile. Moreover, the charge
separated resonance form 1′ (Scheme 1) also reduces the
electrophilicity of the C-4 position.
Even though some 4H-1,2,6-thiadiazin-4-ylidenes have been
prepared,6c,11a to our knowledge nonoxidized 4H-1,2,6-
thiadiazin-4-imines are unknown. As such, in an effort to
expand the available chemistry of this ring system and to access
new chemical structures, we decided to investigate the synthesis
of this new category of 4H-1,2,6-thiadiazines.
Having in mind our previous success with the TiCl4
mediated condensation of 3,5-diaryl-1,2,6-thiadiazin-4-ones 3
with malononitrile,12 we investigated the analogous condensa-
tion with amines. Gratifyingly, reacting 3,5-diphenyl-4H-1,2,6-
thiadiazin-4-one (3a) with aniline (3 equiv) and TiCl4 (3
equiv) in PhMe at 110 °C gave N,3,5-triphenyl-4H-1,2,6-
thiadiazin-4-imine (5) in 91% yield (Scheme 2).
Despite the successful synthesis of the triphenylimine 5, this
Transformation of the C-4 carbonyl to afford an ylidene-
malononitrile can only be achieved when both the 3- and 5-
halogens are replaced first by poor nucleofuges such as aryl
groups and then via a base-free TiCl4-mediated condensation
with malononitrile12 or via a two-step protocol involving
route is limited:12 owing to the relative harshness of TiCl4 this
Received: July 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02237
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Initially, we reacted the tetrachlorothiadiazine 8 with aniline
Scheme 2. Synthesis of N,3,5-Triphenyl-4H-1,2,6-thiadia-
zin-4-imine (5)
(1 equiv) in DCM with the addition of Hunig’s base (2 equiv)
̈
and obtained the desired 3,5-dichloro-N-phenyl-4H-1,2,6-
thiadiazin-4-imine (6a) in a modest 33% yield. A brief
optimization identified MeCN as a better solvent for these
reactions and that using excess aniline (3 equiv) to act as both a
nucleophile and base improved the yield of the imine 6a to 86%
(Table 1, entry 1). The only minor side product isolated from
route cannot readily be applied to thiadiazines substituted at C-
3/5 with electron-rich hetaryls such as the more desirable thien-
2-yl, fur-2-yl, and pyrrol-2-yl systems. A more versatile synthesis
was therefore required to access the thiadiazinimines 6 that can
subsequently be functionalized at the C-3/5 positions.
Table 1. Preparation of N-Aryl-3,5-dichloro-4H-1,2,6-
thiadiazin-4-imines 6 from Tetrachlorothiadiazine 8 (0.42
mmol) with Arylamines (3 equiv) in MeCN at 0−20 °C
The direct synthesis of dichlorothiadiazinimines 6 from
dichlorothiadiazinone 1 was not possible as the 3,5-chlorines
can be easily displaced by amine nucleophiles.10 By recognizing
the structural similarities of the ionic 4,5-dichloro-1,2,3-
dithiazolium chloride (7)13 and the covalent 3,4,4,5-tetra-
chloro-4H-1,2,6-thiadiazine (8) and the potential contribution
of the ionic form 8′ (Scheme 3), we were able to solve this
Scheme 3. Reactions of Dithiazolium 7 and Tetrachloro-
thiadiazine 8 with Anilines
entry
Ar
time (h)
yields of 6 (%)
a
1
Ph
0.50
3
6a (86)
2
2-Tol
6b (84)
6c (84)
6d (81)
6e (76)
6f (96)
6g (61)
6h (95)
6i (88)
6j (93)
6k (74)
6l (92)
6m (74)
6n (84)
6o (87)
6p (89)
6q (83)
6r (90)
6s (84)
6t (91)
6u (73)
6v (43)
3
3-Tol
1
4
4-Tol
0.75
2
5
2-NCC6H4
4-NCC6H4
2-O2NC6H4
4-O2NC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-FC6H4
6
2
7
8
8
2
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
0.67
1
1
2-ClC6H4
3-ClC6H4
4-ClC6H4
2,6-Cl2C6H3
2-BrC6H4
3-BrC6H4
4-BrC6H4
2-IC6H4
3
0.67
1
problem. 4,5-Dichloro-1,2,3-dithiazolium chloride (7) readily
condenses with anilines to give the corresponding N-arylimines
9,13 and in a similar manner, we considered that the
tetrachlorothiadiazine 8, which could be in equilibrium with
its ionic form 8′, should also react with anilines to give the
desired thiadiazinimines 6 (Scheme 3).
24
3
0.67
1
1.5
0.67
2.5
3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (8) is readily pre-
4-IC6H4
11
pared by the reaction of dichloromalononitrile and SCl2 and
4-H2NC6H4
can be isolated by vacuum distillation (bp 90 °C at 30 mbar)
and stored for several months at −40 °C in the absence of air
and moisture. While the compound has been known for over
40 years, its chemistry to date was limited to the reaction with
98% formic acid to give the thiadiazinone 110 and to its
degradation in moist air to give 2-chloromalonamide.14
Presumably, while both thiadiazines 1 and 8 are highly
electrophilic and have multiple sites of reactivity toward
nucleophiles, halophiles, and thiophiles, it is the nonaromatic
nature of the latter which contains an sp3 hybridized carbon at
C-4, which makes the ring more labile to hydrolytic
fragmentation. Potentially, this has deterred researchers from
further investigating this compound as a scaffold in the
synthesis of thiadiazines or other heterocycles. Herein, we
identify facile conditions for the regioselective reactions of
thiadiazine 8 with anilines and demonstrate the subsequent
modification of the remaining C-3/5 positions via direct
nucleophilic substitution and Stille coupling chemistry.
a
Bis-adduct 10 also isolated 3%.
the reaction was 3-anilino-5-chloro-N-phenyl-4H-1,2,6-thiadia-
zin-4-imine (10), in a low 3% yield. While the use of excess
aniline was not atom economic, it could be recovered as its
hydrochloride salt in near-quantitative yields. By using these
optimized reaction conditions, a range of analogues were
prepared in good to excellent yields (Table 1).
In general, the reaction worked well with a variety of primary
anilines but failed for primary alkylamines. Interestingly, both
steric and electronic effects were observed: the reactions of
anilines bearing ortho substituents were slower but with little or
no effect on the product yield. The presence of the bulky ortho
nitro group [Table 1, entry 7, A(NO2) = 1.05 kcal/mol]15 gave
a suppressed yield of only 61%, while the hindered 2,6-
dichloroaniline gave the longest reaction time (24 h) but a
good yield of imine 6p (89%, Table 1, entry 16). Anilines
B
DOI: 10.1021/acs.orglett.5b02237
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bearing electron-withdrawing substituents such as cyano, nitro,
and fluoro in the para position gave excellent yields of imine
(Table 1, entries 6, 8, 12, respectively), while electron-donating
substituents such as para-MeO gave slightly reduced yields.
This can be attributed to the higher nucleophilicity of electron-
rich anilines that can lead to side reactions that degrade the
starting tetrachlorothiadiazine 8, e.g., thiophilic attack. Interest-
ingly, reaction of tetrachlorothiadiazine 8 with 1,4-diamino-
benzene (3 equiv) using identical conditions yielded the
bisthiadiazine 6v in 43% yield (Table 1, entry 22).
Unfortunately, reactions with hetarylamines, such as pyridyl-,
pyrimidyl-, and pyrazinylamines, degraded the starting material.
This was tentatively attributed to the basicity of these amines
since during our optimization studies tetrachlorothiadiazine 8
was unstable to the presence of nonhindered pyridine bases.
To assess the reactivity of these imines, their stability and
functionalization at the C-3/5 positions was investigated. 3,5-
Dichloro-N-phenyl-4H-1,2,6-thiadiazin-4-imine (6a) was
shown by single crystal X-ray crystallography to adopt a
shallow boat conformation (Figure 1) and to be weakly
aromatic (IA = 49; cf. IA = 53 for furan and 100 for benzene).16
Table 2. Reactions of the Thiadiazinimine 6a with
Nucleophiles
a
entry
conds.
R
time (h)
product (%)
1
2
3
4
5
6
a
b
c
d
e
f
MeO
MeO
0.5
1
11 (83)
12 (90)
13 (76)
14 (89)
5 (92)
morpholin-4-yl
morpholin-4-yl
Ph
2
72
0.5
1
thien-2-yl
15 (93)
a
Conditions: (a) NaOMe (1 equiv), MeOH, 0 °C; (b) NaOMe (2
equiv), MeOH, 0−20 °C; (c) morpholine (2 equiv), MeCN, 20 °C;
(d) morpholine (8 equiv), neat, 20 °C; (e) PhSnBu3 (2.2 equiv),
Pd(Ph3P)2Cl2 (5 mol %), PhMe, Ar, 110 °C; (f) (Thien-2-yl)SnBu3
(2.2 equiv), Pd(Ph3P)2Cl2 (5 mol %), PhMe, Ar, 110 °C.
morpholine (8 equiv) at ca. 20 °C for 3 days, to afford the
desired product 14 in 89% yield (Table 2, entry 4).
Furthermore, Stille and Suzuki couplings of 3,5-dichloro-N-
phenyl-4H-1,2,6-thiadiazin-4-imine (6a) were investigated.
Stille coupling with PhSnBu3 (2.2 equiv) using catalytic
Pd(Ph3P)2Cl2 (5 mol %) was successful, and the best results
were obtained when the reaction was performed in dry PhMe at
ca. 110 °C giving the product N,3,5-triphenyl-4H-1,2,6-
thiadiazin-4-imine (5) in 92% yield while coupling with
(thieny-2-yl)SnBu3 under similar conditions gave the 3,5-
di(thien-2-yl)thiadiazine 15 in excellent yield (Table 2, entries
5 and 6, respectively). Unfortunately, Suzuki couplings with
PhB(OH)2 in both aqueous11b and anhydrous17 conditions led
to degradation of the starting material.
In conclusion, 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (8)
readily condenses with anilines at the C-4 position to afford the
thiadiazinimines 6a−v in 43−96% yields. Furthermore, the C-3
and C-5 chlorines of 3,5-dichloro-N-phenyl-4H-1,2,6-thiadia-
zin-4-imine (6a) were displaced by morpholine and methoxide
to give mono- and/or bis-displacement products. Finally, the
Stille coupling reactions of thiadiazinimine 6a with PhSnBu3
and (thieny-2-yl)SnBu3 gave the corresponding 3,5-diarylated
imines 5 and 15 in 92% and 93% yields, respectively. This
paper describes the first use of the tetrachlorothiadiazine 8 for
preparing thiadiazinimines and highlights the potential of this
unexplored reagent.
Figure 1. Geometry of 3,5-dichloro-N-phenyl-4H-1,2,6-thiadiazin-4-
imine (6a) (CCDC-1407948) in the crystal and the crystallographic
atom numbering. Thermal ellipsoids are shown at 50% probability.
Hydrogens are omitted for clarity.
The imine 6a was stable in the solid phase up to 196 °C
(DSC mp: onset 71.2 °C, peak max 71.8 °C, decomp. onset
197.0 °C, peak max 199.0 °C), while in solution it was stable in
EtOH or PhMe heated at reflux for 24 h and also in biphenyl
heated at 200 °C for 24 h. The imine 6a was also stable in a
dilute solution of trialkylamines (Et3N 2 equiv in MeCN at ca.
20 °C), while in the presence of 2 M HCl, in THF/H2O at ca.
20 °C, the imine hydrolyzed to give the thiadiazinone 1 in 93%
yield.
Reaction of the imine 6a with NaOMe in MeOH at ca. 0 °C
led to a fast displacement of the C-3 chlorine to give 3-chloro-
5-methoxy-N-phenyl-4H-1,2,6-thiadiazin-4-imine (11) (as a
mixture of E and Z isomers) in 83% yield, while using 2
equiv of methoxide yielded the dimethoxythiadiazine 12 in
good yield (Table 2, entries 1 and 2, respectively). Reaction of
the imine 6a with morpholine (2 equiv) in MeCN at ca. 20 °C
led to a fast displacement of the C-3 chlorine giving the 3-
morpholinothiadiazine 13 in 76% yield (Table 2, entry 3). Not
surprisingly, owing to electron release from the first morpho-
line, the displacement of the second chlorine was more difficult
and was achieved by treating the imine 6a with neat
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02237.
Experimental Section, X-ray data for imine 6a, and NMR
spectra (PDF)
CIF for imine 6a (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Koutenti@ucy.ac.cy.
C
DOI: 10.1021/acs.orglett.5b02237
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank I. J. Stavrou and C. P. Kapnissi-
Christodoulou (University of Cyprus) for ESI-APCI+ mass
spectra and the Cyprus Research Promotion Foundation
(Grants: ΣTPATHII/0308/06, NEKYP/0308/02 YΓEIA/
0506/19, and ENIΣX/0308/83).
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DOI: 10.1021/acs.orglett.5b02237
Org. Lett. XXXX, XXX, XXX−XXX