The Reaction of 6-(4-Chloro-5 H -1,2,3-dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one with Benzene-1,2-diamine: Synthesis and Chemistry of N -(2-Aminophenyl)-2-hydroxy-5-methylbenzimidoyl Cyanide

Article abstract of DOI:10.1055/s-0039-1690246

(Z)-6-(4-Chloro-5 H -1,2,3-dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one, readily prepared from 4,5-dichloro-1,3,4-dithiazolium chloride and p -cresol, reacts with benzene-1,2-diamine to give N -(2-aminophenyl)-2-hydroxy-5-methylbenzimidoyl cyanid

Full text of DOI:10.1055/s-0039-1690246

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
M. Koyioni, P. A. Koutentis
Letter
Synlett
The Reaction of 6-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-4-meth-
ylcyclohexa-2,4-dien-1-one with Benzene-1,2-diamine: Synthesis
and Chemistry of N-(2-Aminophenyl)-2-hydroxy-5-methylbenzim-
idoyl Cyanide
Maria Koyioni*
0
0
0
0-0
0
0
2-2
7
8
6-
7
5
2
3
NH2
Me
Panayiotis A. Koutentis
OH
OH
O
NH2
N
N
N
+
+
Me
Me
Me
Department of Chemistry, University of Cyprus, P.O. Box
20537, 1678 Nicosia, Cyprus
mkogio01@ucy.ac.cy
Cl
N
HN
O
H2N
N
S
N
S
AcOH, reflux
up to 59%
HCO2H, rt
up to 90%
AcOH, rt
up to 70%
Received: 14.10.2019
Accepted after revision: 21.10.2019
Published online: 05.11.2019
developing Xenopus embryos17 by 1,2,3-dithiazolimines
have also recently been reported. Dithiazolimines 2a also
find use in synthesis. Recent developments include ring
transformations to pyrazolo[3,4-d]thiazoles,18 pyridothi-
azoles,19 pyrido[2,3-d]pyrimidines,20 and the rare 1,2,4-
dithiazines.21
The synthesis and chemistry of 5H-1,2,3-dithiazol-5-
ylidenes 2b, which can be derived from the reaction of Appel
salt 1 with either active methylene compounds or aromatic
enols, are much less explored than their imine counterparts
2a. Nevertheless, active methylene compound-derived di-
thiazolylidenes are numerous. Examples include ylidene-
malononitrile 3,22–24 alkyl (dithiazolylidene)-2-cyanoace-
tates 4,1 5-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2,2-di-
methyl-1,3-dioxane-4,6-dione (5),25 3-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-1,1,1-trifluoropropan-2-ones 6,26 and
4-chloro-5-(diphenylmethylene)-5H-1,2,3-dithiazole (7)25
(Figure 1). Dithiazolylidenes not derived from Appel salt 1
have also been reported.27
DOI: 10.1055/s-0039-1690246; Art ID: st-2019-d0545-l
Abstract (Z)-6-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylcy-
clohexa-2,4-dien-1-one, readily prepared from 4,5-dichloro-1,3,4-dithi-
azolium chloride and p-cresol, reacts with benzene-1,2-diamine to give
N-(2-aminophenyl)-2-hydroxy-5-methylbenzimidoyl cyanide. The lat-
ter, in acidic media, cyclizes to give, depending on the reaction condi-
tions, 2-methylbenzofuro[2,3-b]quinoxaline, 2-(1H-benzo[d]imidazol-
2-yl)-4-methylphenol or 2-(3-aminoquinoxalin-2-yl)-4-methylphenol.
Key words 1,2,3-dithiazole, imidazole, quinoxaline, benzofuran, ion-
izing power, carboxylic acid, heterocycle, cyclization
4,5-Dichloro-1,2,3-dithiazolium chloride (Appel salt;
1),1,2 prepared around 35 years ago, is the most well-known
aromatic dithiazole and the starting material for many neu-
tral 5H-1,2,3-dithiazoles 2 by reaction with various nucleo-
philes (Scheme 1).3–6
Me
X
Cl
Cl
Cl
2a, X = NAr
2b, X = CR2
2c, X = O
Me
O
H2X
O
CN
S
CN
S
S
N
S
N
RO
O
S
S
2d, X = S
Cl
Cl
Cl
NC
Cl
O
O
N
N
S
N
1
2
S
S
S
Scheme 1 Reaction of Appel salt 1 with nucleophiles
3
4
5
R
For example, reaction of Appel salt 1 with (hetero)aro-
matic amines provides access to 5H-1,2,3-dithiazol-5-
imines 2a, the most well studied category of neutral 1,2,3-
dithiazoles to date. Several dithiazolimines 2a display prop-
erties such as antitumor,7 antibacterial,8–11 antifungal,9,12–14
and herbicidal activity.15 Inactivation of the glutamine/ami-
no acid transporter ASCT2,16 and elicited pigment loss on
F3C
Cl
Cl
O
S
N
S
N
S
S
6
7
Figure 1 Structures of known 1,2,3-dithiazolylidenes
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Koyioni, P. A. Koutentis
Letter
Synlett
Several dithiazolylidenes undergo useful ring transfor-
mations, such as the conversion of ylidenemalononitrile 3
into 3-haloisothiazole-5-carbonitriles;28 2,2-dimethyl-1,3-
dioxane-4,6-dione 5 into 6-carbamoyl-5-oxo-5H-furo[2,3-
d][1,2,3]dithiazoles;29 1,1,1-trifluoropropan-2-ones 6 into
2,5-dihydro-2-iminopyrroles and furans,30 and diphenyl-
methylene 7 into 3-phenylbenzo[b]thiophene-2-carboni-
trile.25
In contrast to dithiazolylidenes derived from active
methylene compounds, only one aromatic enol-derived
dithiazolylidene was known until recently; that being (Z)-
6-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylcyclo-
hexa-2,4-dien-1-one (8). The high-yielding synthesis of
ylidene 8, from Appel salt 1 and p-cresol, and its hydrolysis
to benzofuran-2,3-dione (9) and 2-hydroxybenzoic acid
(10) were reported by Appel in 1985 (Scheme 2).1 Since
then, to our knowledge, no other ylidene 8 chemistry has
been reported.
Me
YH
CN
Me
X
Me
S
Me
Cl
YH2
– S8
– HCl
H2X
O
C N
O
XH
Y
HO
HY
N
YH
S
XH2
8
NH
XH
11
HO
Scheme 3 Envisioned reactivity of dithiazolylidene 8 with bis-nucleo-
philes
that crystallized as bright-red needles from cyclohexane.32
Mass spectrometry (m/z 252 [M + H]+), and elemental anal-
ysis supported the molecular formula C15H13N3O. FTIR spec-
troscopy revealed the presence of a cyano group [max
(C≡N) 2222 cm–1], and two different O/N-H groups [max
O
EtOH, H2O
heating
Me
O
Me
O
(O/N-H) 3483 and 3379 cm–1]. H NMR spectroscopy indi-
1
Cl
Cl
HO
Me
cated seven aromatic resonances integrating to a total of
seven protons. In addition, two broad resonances corre-
sponding to exchangeable acidic protons were observed at
12.25 (1 H) and 3.97 ppm (2 H), indicating the presence of a
phenolic hydroxyl and an amino group, respectively.
Based on the data, the product was tentatively identi-
fied as N-(2-aminophenyl)-2-hydroxy-5-methylbenzimi-
doyl cyanide (12). Nevertheless, its red-bright color [max
450 nm (log  4.03)] was intriguing and the presence of a
quinoidal form 12′ could not be ruled out. To study the ori-
gin of the red color we performed TD-DFT calculations, at
the B3LYP/6-311G(d,p) level of theory, for both the pheno-
lic 12 and quinoidal form 12′ (Scheme 4).
Cl
9
S
N
O
S
S
N
O
Cl
S
Me
NaOH
OH
OH
1
8
10
Scheme 2 Synthesis and known chemistry of (Z)-6-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one (8)
Recently, we expanded this family of dithiazolylidenes to
analogues of electron-rich pyridols,16 and, in 2018, Thiéry et
al. reported the reaction of Appel salt 1 with indolin-2-
ones.31
OH
O
The absence of additional chemistry of dithiazolylidene
8 is surprising. Compound 8 has a deep-purple color, owing
partly to its ortho-quinone methide structure, and to a
strong contribution of a charge-separated resonance form.
Furthermore, it hosts a latent aromatic ring that, on reac-
tion with nucleophiles, can be restored. We hypothesized
that reaction of ylidene 8 with a nucleophile could give in-
termediate 11, which has numerous electrophilic sites and,
in the presence of a tethered nucleophile, at least three dif-
ferent products could form (Scheme 3). In light of this, we
initiated studies on the reaction of ylidene 8 with bis-nucle-
ophiles.
Herein, we report the reaction of (Z)-6-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one
(8) with benzene-1,2-diamine and reveal some preliminary
chemistry of the initially formed product.
The reaction of benzene-1,2-diamine with dithi-
azolylidene 8 in DCM with DBU as base gave no cyclization
products. Instead, a red colored product 12 was isolated
NH2
NH2
H
N
N
Me
Me
CN
12
CN
12'
Scheme 4 The structure of N-(2-aminophenyl)-2-hydroxy-5-methyl-
benzimidoyl cyanide (12) and its quinoidal form 12′
TD-DFT calculations gave a max of 481 nm for the phe-
nolic form 12 and 525 nm for the quinoidal 12′. In addition,
the energy calculations showed that the phenolic form 12 is
5.9 kcal mol–1 more stable than the quinoidal form 12′.
These results further support the proposition that the prod-
uct has the structure of phenol 12. In addition, the TD-DFT
calculations suggest that the lowest excitation energy is as-
sociated with a HOMO→LUMO transition. Analysis of the
orbital distribution for the HOMO and LUMO in compound
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
M. Koyioni, P. A. Koutentis
Letter
Synlett
12 revealed a charge-transfer process from the amino to the
cyano group (Figure 2), which could be responsible for the
bright-red color of the molecule.
Unable to obtain cyclization products under the above
reaction conditions, we investigated the reactivity of benz-
imidoyl cyanide 12 in different media and interesting re-
sults were observed in neat carboxylic acids as solvent.33
A
solution of compound 12 in AcOH at room temperature
gave, after four hours, three products: 2-methylbenzofu-
ro[2,3-b]quinoxaline (13),34 2-(1H-benzo[d]imidazol-2-yl)-
4-methylphenol (14)35 and 2-(3-aminoquinoxalin-2-yl)-4-
methylphenol (15), in <1, 23, and 62% yield, respectively
(Table 1, entry 1). Increasing the reaction time (up to 14 h)
did not significantly affect the product yields (entry 2). In-
creasing the temperature to 118 °C (refluxing AcOH) gave,
as the major product, benzofuroquinoxaline 13 (62%) with
a concomitant decrease in yield for the aminoquinoxaline
15 (traces) (entry 3); the yield of benzimidazole 14 re-
mained unaffected. This indicated that aminoquinoxaline
15 was an intermediate in the formation of benzofuroqui-
noxaline 13. Further support for this view was provided
when a pure sample of aminoquinoxaline 15 heated in
AcOH at 118 °C, gave benzofuroquinoxaline 13 in near
quantitative yield (Scheme 6).
Figure 2 HOMO and LUMO molecular orbital representations for com-
pound 12
The reaction was partially optimized. The use of stoi-
chiometric amounts of benzene-1,2-diamine (1 equiv) and
DBU (1 equiv) led to a long reaction time (>6 h) and a mod-
erate product yield (44%). A slight excess of benzene-1,2-di-
amine and DBU (1.1 or 1.25 equiv) significantly reduced the
reaction time (10–15 min), but the product yield remained
moderate (49% and 65%, respectively). With 1.5 equiv of
DBU and benzene-1,2-diamine the reaction was complete
within 10 minutes and the product was obtained in very
good yield (70%; Scheme 5). Further increasing the number
of equivalents (2 equiv) had no effect on product yield (5
min, 70% yield).
OH
O
AcOH
N
N
N
ca. 118 °C, 6.5 h
Me
Me
N
98%
H2N
15
13
Scheme 6 Transformation of 2-(3-aminoquinoxalin-2-yl)-4-methyl-
phenol (15) into 2-methylbenzofuro[2,3-b]quinoxaline (13)
Me
OH
DBU (1.5 equiv)
NH2
NH2
NH2
Cl
DCM, ca. 20 °C, 10 min
When HCO2H was used as solvent the selectivity com-
pletely reversed and benzimidazole 14 was obtained as the
main product (90% yield) with only traces of benzofuroqui-
noxaline 13 (Table 1, entry 4).
N
+
Me
O
70%
S
N
CN
S
8
12
(1.5 equiv)
This switch in selectivity can be tentatively attributed to
the different ionizing powers of acetic and formic acids; i.e.,
the ability of the solvent to promote ionization of a species
by an SN1-type process.36 Notably, formic acid is second
Scheme 5 Reaction of 1,2,3-dithiazolylidene 8 with benzene-1,2-di-
amine
Table 1 Transformations of N-(2-Aminophenyl)-2-hydroxy-5-methylbenzimidoyl Cyanide (12) in AcOH and HCO2H
OH
OH
O
OH
NH2
N
N
N
N
+
+
Me
Me
Me
Me
N
HN
CN
12
H2N
N
13
14
15
Entry
Solvent
Time (h)
Temp (°C)
Yield (%)
13
14
15
62
70
trace
0
1
2
3
4
AcOH
AcOH
AcOH
HCO2H
4.17
14
5
20
trace
trace
59
23
24
20
90
20
118
20
1
trace
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
M. Koyioni, P. A. Koutentis
Letter
Synlett
OH
C
OH
N
OH
NH2
Path A
HCN
Me
Me
N
N
Me
C
N
H2N
H2N
CN
12
16
Path B
HCN
6-exo-dig
5-exo-dig
OH
OH
OH
5-endo-dig
N
Me
N
Me
15
Me
N
HN
HN
N
H
H2N
17
14
15'
Scheme 7 Speculative mechanistic pathways to explain the change in selectivity observed when acetic acid is switched to formic acid
only to water in ionizing power.36 The dramatic differences
between the ionizing powers of AcOH vs. HCO2H and the ef-
fect on reaction outcomes is well documented, for instance
in the solvolysis of cis-cyclooctene oxide,37 the ionization of
organic chlorides,38 and the solvolysis of 1-adamantyl io-
dide.39 Based on these differences, we tentatively propose
that, in the case of AcOH, the mechanism proceeds via a 6-
exo-dig cyclization by nucleophilic attack of the amine onto
the cyano group to give quinoxalinimine 15′, whereas in
HCO2H ionization of compound 12 to the cation 16 or 17, by
assistance of the oxygen or nitrogen lone pair, respectively,
precedes cyclization, which then favors exclusive formation
of benzimidazole 14 (Scheme 7). Mechanistic investigations
are under way to understand the observed reactivities better.
To conclude, the reaction of (Z)-6-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one(8)
with benzene-1,2-diamine gives N-(2-aminophenyl)-2-hy-
droxy-5-methylbenzimidoyl cyanide (12) as the major
product in very good yield. In acidic media, compound 12
gives three different products: 2-methylbenzofuro[2,3-
b]quinoxaline (13), 2-(1H-benzo[d]imidazol-2-yl)-4-meth-
ylphenol (14), and 2-(3-aminoquinoxalin-2-yl)-4-methyl-
phenol (15). Each product can be formed in high yield by
careful selection of solvent and temperature. The products
formed are potentially useful heterocyclic scaffolds,40 and
the scope of the reaction is currently under examination.
References and Notes
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V.; Taylor, R. J. K., Ed.; Elsevier: Oxford, 2008, Chap 6.01, 1–36.
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Acknowledgment
We thank Dr Georgia A. Zissimou for the execution of the theoretical
calculations.
(18) Koyioni, M.; Manoli, M.; Manolis, M. J.; Koutentis, P. A. J. Org.
Chem. 2014, 79, 4025.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690246.
S
u
p
p
orit
n
gInformati
o
n
S
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p
p
orti
n
gInformati
o
n
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

E
M. Koyioni, P. A. Koutentis
Letter
Synlett
(21) Koyioni, M.; Manoli, M.; Koutentis, P. A. J. Org. Chem. 2014, 79,
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(500 MHz, CDCl3):  = 12.25 (s, 1 H, OH), 7.67 (d, J = 1.0 Hz, 1 H,
ArH), 7.30–7.25 (m, 2 H, ArH), 7.20 (dd, J = 8.0, 1.0 Hz, 1 H, ArH),
6.97 (d, J = 8.5 Hz, 1 H, ArH), 8.67–8.63 (m, 2 H, ArH), 2.37 (s,
3 H, CH3). 13C NMR (125 MHz, CDCl3):  = 158.6 (s), 141.8 (s),
140.6 (s), 135.9 (d), 132.5 (s), 130.4 (d), 130.1 (d), 129.3 (s),
120.4 (d), 118.6 (d), 117.9 (d), 117.1 (s), 116.1 (d), 110.3 (s), 20.5
(q). MALDI-TOF MS: m/z (%) = 252 (100) [M + H]+, 225 (75).
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(33) General procedure: A solution of N-(2-aminophenyl)-2-
hydroxy-5-methylbenzimidoyl cyanide (12; 30.0 mg, 0.12
mmol) in the appropriate carboxylic acid (3.0 mL) was stirred at
the appropriate temperature (Table 1) until complete consump-
tion of the starting material (indicated by TLC). After comple-
tion of the reaction, the mixture was poured onto crushed ice
and neutralized by careful addition of aqueous NaHCO3. The
aqueous phase was extracted with DCM (4 × 20 mL) and the
combined organic extracts were dried (Na2SO4), filtered and
evaporated. The remaining residue was adsorbed onto silica and
purified by chromatography to give the corresponding products.
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(40) For examples of reported biological activities of structurally
similar compounds, see: (a) Adegboye, A. A.; Khan, K. M.; Salar,
U.; Aboaba, S. A. Kanwal, Chigurupati, S.; Fatima, I.; Taha, M.;
Wadood, A.; Mohammad, J. I.; Khan, H.; Perveen, S. Eur. J. Med.
Chem. 2018, 150, 248. (b) You, L.; Cho, E. J.; Leavitt, J.; Ma, L.-C.;
Montelione, G. T.; Anslyn, E. V.; Krug, R. M.; Ellington, A.;
Robertus, J. D. Bioorg. Med. Chem. Lett. 2011, 21, 3007. (c) Deady,
L. W.; Kaye, A. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. J. Med.
Chem. 1997, 40, 2040.
(28) Kalogirou, A. S.; Christoforou, I. C.; Ioannidou, H. A.; Manos, M.
J.; Koutentis, P. A. RSC Adv. 2014, 4, 7735.
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(30) Lee, H.-S.; Kim, K. Tetrahedron Lett. 1998, 39, 6895.
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Chérouvrier, J.-R.; Domon, L.; Besson, T.; Thiéry, V. Molecules
2018, 23, 1390.
(32) To a stirred solution of (Z)-6-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-4-methylcyclohexa-2,4-dien-1-one (8; 20.0 mg, 0.082
mmol) and benzene-1,2-diamine (13.3 mg, 0.123 mmol) in dry
DCM (5 mL) was added dry DBU (18.5 L, 0.123 mmol, 1.5
equiv) in one portion. After complete consumption of the start-
ing material (10 min, by TLC) the reaction mixture was poured
onto a packed column of silica and purified by chromatography
(n-hexane/DCM, 10:90) to give N-(2-aminophenyl)-2-hydroxy-
5-methylbenzimidoyl cyanide (12; 14.4 mg, 70%) as bright-red
needles; mp (hot stage): 151–153 °C (from cyclohexane); Rf
0.62 (DCM). Anal. Calcd (%) for C15H13N3O: C, 71.70; H, 5.21; N,
16.72. Found: C, 71.61; H, 5.31; N, 16.54. UV: max (DCM) = 229
(log  4.29), 245 (4.28), 261 (4.27), 291 (4.33), 412 inf (3.96),
450 nm (4.03). IR: 3483m, 3379m, 3034w (aryl C-H), 2924m
and 2853w (alkyl C-H), 2222w (C≡N), 1628m, 1580m, 1537m,
1487s, 1458m, 1389m, 1317m, 1294m, 1275m, 1254m, 1231m,
1192m, 1157m, 1144m, 1099w, 1065w, 1034w, 1022m, 989m,
955w, 928m, 905m, 868m, 843m, 814m, 789m cm–1 1H NMR
.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E