Synthesis of new pentacyclic diquinothiazines

Article abstract of DOI:10.1002/jhet.5570440307

(Chemical Equation Presented) Reactions of 2,2′-dichloro-3,3′- diquinolinyl sulfide 1 with ammonia derivatives and various primary alkylamines and arylamines proceeded as a thiazine ring closure to form linear annulated pentacyclic 6H-diquinothiazine 2H and 6-substituted derivatives 2 with alkyl, alkylaryl, aryl and heteroaryl substituents in moderate to good yields. Reaction with 2-chloroethylamine did not stop at the formation of half-mustard derivative 2k but ran to ethylenediquinothiazinium salt 11. 6H-Diquinothiazine 2H was N-alkylated and N-arylated to give 6-substituted derivatives 2. The crucial substrate 1 was obtained from other heteropentacenes 3 and 4 via 1,4-dithiin ring opening and further transformations. X-ray analysis of p-nitrophenyldiquinothiazine 2i revealed unexpected planar thiazine ring.

Full text of DOI:10.1002/jhet.5570440307

May-Jun 2007
543
Synthesis of New Pentacyclic Diquinothiazines [1]
Maꢀgorzata Nowaka, Krystian Plutaa,*, Kinga Suwiꢁskab and Leo Straverc
,
a Department of Organic Chemistry, The Medical University of Silesia, Jagielloꢁska 4, 41-200 Sosnowiec,
Poland. E-mail: pluta@slam.katowice.pl
b Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
c Bruker AXS B.V., Oostsingel 209, 2612 HL Delft, Netherlands
Received March 14, 2006
S
S
S
N
N
N
N
N
N
H
N
2H
3
S
S
N
N
R
N
Cl
Cl
2
1
Reactions of 2,2'-dichloro-3,3'-diquinolinyl sulfide 1 with ammonia derivatives and various primary
alkylamines and arylamines proceeded as a thiazine ring closure to form linear annulated pentacyclic 6H-
diquinothiazine 2H and 6-substituted derivatives 2 with alkyl, alkylaryl, aryl and heteroaryl substituents in
moderate to good yields. Reaction with 2-chloroethylamine did not stop at the formation of half-mustard
derivative 2k but ran to ethylenediquinothiazinium salt 11. 6H-Diquinothiazine 2H was N-alkylated and N-
arylated to give 6-substituted derivatives 2. The crucial substrate 1 was obtained from other hetero-
pentacenes 3 and 4 via 1,4-dithiin ring opening and further transformations. X-ray analysis of p-nitro-
phenyldiquinothiazine 2i revealed unexpected planar thiazine ring.
J. Heterocyclic Chem., 44, 543 (2007).
[12]. In the search of biologically active and semiconduc-
tive heterocycles a series of triazathiapentacenes being
linear condensed pentacyclic diquino-1,4-thiazines has
been synthesized.
INTRODUCTION
Phenothiazines attract attention because of their wide
chemical properties and very interesting biological acti-
vities (antipsychotic and anticancer). Some modifications
of the phenothiazine structures were directed into azaphe-
nothiazines, where the benzene ring was substituted with
an azine ring [2]. In continuation of our search for phar-
macoactive quinoline derivatives we modified the pheno-
thiazine structure with the quinoline ring to obtain diqui-
no-1,4-thiazines being pentacyclic dibenzodiazapheno-
thiazines [3,4]. It is worth noting that pentacyclic carbo-
cycles and heterocycles (pentacenes and pentaphenes) are
considered as a new types of electron donors [5-9] and
show the significant conductivity [10] and photoelectric
properties [11] and are the active layer in a FET device
RESULTS AND DISCUSSION
Synthesis. In our previous paper [13] we found 2,2'-
dichloro-3,3'-diquinolinyl sulfide 1 to be very promising
substrate to obtain various types of heteropentacenes in the
heterocyclic ring (1,4-dithiin, 1,4-oxathiin, 1,4-thiaselenin,
thiopyran and 1,4-thiazine) closure reactions with various
reagents. The reaction of sulfide 1 with methylamine in hot
phenol and with aniline in boiling monomethyl ether of
diethylene glycol (MEDG) led to 6-methyl- and 6-phenyl-
diquino[3,2-b;2',3'-e][1,4]thiazines 2a and 2b. In this paper
S
S
S
[MeSC(NH2)NH2]2SO4
LiOH, DMSO, 70oC
DMSO, NaOH
MeI
N
N
S
N
N
N
6
N
N
7
SMeNaS
SMeMeS
3
140oC
EtOH/POCl3
NaS
S
S
S
[MeSC(NH2)NH2]2SO4
LiOH, DMSO, 70oC
N
S
4
N
N
N
Cl
Cl
5
1
N
SMe
Scheme 1

544
M. Nowak, K. Pluta, K. Suwiꢀska and L. Straver
Vol 44
we describe the synthesis of 6H-diquinothiazine 2H and
carried out in MEDG. The reaction of sulfide 1 with
methylamine hydrochloride (5 equivalents) in MEDG
gave diquinothiazine 2a in higher yield (76%) than in
phenol (51%) and without by-product 9 [13]. Reaction
with butylamine gave 6-butyldiquinotiazines 2c in low
yield (17%) but repeated in an autoclave gave better yield
(59%). Reactions with benzylamine led to benzyldiquino-
thiazine 2d and open ring product – sulfide 10 depending
on the reaction conditions and amounts of amine
(Table 1).
The reactions with 3 equivalents of aromatic amines,
being para-substituted anilines, (p-toluidine, 4-chloroanil-
ine, 4-bromoaniline, 4-aminobenzoic acid) gave 6-aryldi-
quinothiazines 2e-2h in moderate to good yield (61-82%,
Table 1). The reaction with 4-nitroaniline gave (4'-nitro-
phenyl)diquinothiazine 2i in very low yield (10%) but
better yield was achieved in an autoclave (56%). The
reaction with heteroaromatic amine, 2-aminopyridine, in
MEDG gave no product but in phenol at 180°C gave (2'-
pyridyl)diquinothiazine 2j in very low yield (11%) and
sulfide 9 as the main product (63%). Repeating the
reaction in boiling 1-methyl-2-pyrrolidinone (MP, 202°C)
did not bring better yield (Scheme 3).
Reaction of sulfide 1 with 2-chloroethylamine to give
nitrogen half-mustard derivative 2k led to compound
possessing different properties from diquinothiazines 2a-
2j. This product first of all was soluble in water and the
Beilstein test and the reaction with silver nitrate showed
the chlorine atom in the molecule of anionic nature. The
1H NMR spectrum revealed unsymmetrical structure since
both quinoline proton signals were nonequivalent. All
these data suggest the product structure as 5,6-ethylenedi-
quinothiazinium chloride 11 formed from diquinothiazine
2k by N-alkylation of one of the quinoline nitrogen atoms
with reactive 2-chloroethyl group (Scheme 4).
various 6-substituted diquinothiazines
alkylaryl, aryl and heteroaryl substituents.
2 with alkyl,
The crucial substrate 1 was obtained in the reaction of
1,4-dithiin ring opening in isomeric heteropentacenes
(diquino-1,4-dithiins) 3 and 4 with S-methylisothiouro-
nium sulfate in the presence of sodium hydroxide in
DMSO at 70°C or 140°C followed by methylation with
methyl iodide to give sulfide 7 which next was
chlorinated with phosphoryl chloride in ethanol solution
(Scheme 1). The use of S-methylisothiouronium sulfate
made it possible to avoid working with very odorous
sodium methanethiolate. In case of the reaction of hetero-
pentacene 4 the dithiin ring opening was accompanied by
the Smiles rearrangement of unusual type (SꢀS, the
quinoline moiety migrated from one sulfur atom to
another) of the resulting sulfide 5 to sulfide 6.
In order to obtain 6H-diquinothiazine 2H we examined
reactions of sulfide 1 with various ammonia derivatives.
First of all we carried reactions in the conditions found for
the annulation reactions of the isomeric sulfide – 4,4'-di-
chloro-3,3'-diquinolinyl [3]. In the reaction of sulfide 1
with ammonium carbonate in MEDG at 194°C we
obtained the annulated product – diquinothiazine 2H in
only 10% yield and the main product was the disub-
stituted compound – 2,2'-diamino-3,3'-diquinolinyl 8 in
44% yield. Similar result was obtained when sulfide 1
was reacted with gaseous ammonia in hot phenol (180°C)
giving diquinothiazine 2H in 13% yield and 2,2'-
diphenoxy-3,3'-diquinolinyl 9 in 39% yield. Only the
reaction of sulfide 1 with potassium carbonate in
acetamide at 180°C gave the annulated product 2H in
moderate yield (57%) (Scheme 2).
In order to obtain 6-substituted diquinothiazines 2
annulation reactions with alkyl and aryl amines were
13
S
11
12
14
1
S
2
10
9
(NH4)2CO3
+
3
MEDG, 194oC
N
7
N
N5
N
N
H 6
NH2 H2N
8
4
8
2H
S
NH3, phenol
180oC
2H
2H
1
+
N
N
OPh PhO
9
MeCONH2,
K2CO3, 180oC
Scheme 2
S
S
RNH2
1
+/ or
N
N
N
N
N
R
R
R
2a, 2c - 2j
9, 10
9 R = OPh
10 R = NHCH2Ph
Scheme 3

May-Jun 2007
Synthesis of New Pentacyclic Diquinothiazines
545
Table 1. Reactions of 2,2'-dichloro-3,3'-diquinolinyl sulfide 1 with aliphatic and aromatic amines
No
Amine (mmol)
Solvent, temp. (oC)/
time (hours)
Products: diquinothiazines 2, 11,
sulfides 9, 10, R, (yield, %)
2a R = CH3 (76)
1
2
3
methylamine x.HCl (5)
butylamine (5)
MEDG, reflux/3
MEDG, reflux/3
MEDG, 180/3, autoclave
MEDG, reflux/3
2c R = CH2CH2CH2CH3 (17)
2c R = CH2CH2CH2CH3 (59)
2d R = CH2C6H5 (33), 10 (40)
2d R = CH2C6H5 (45), 10 (23)
10 R = NHCH2C6H5 (84)
2e R = p-C6H4CH3 (61)
butylamine (3)
4
benzylamine (5)
5
6
benzylamine (3)
benzylamine (10)
p-toluidine (3)
MEDG, 180/3, autoclave
MEDG, 180/3, autoclave
MEDG, reflux/4
7
8
9
4-chloroaniline (3)
4-bromoaniline (3)
4-aminobenzoic acid (3)
4-nitroaniline (3)
4-nitroaniline (3)
2-aminopyridine (3)
2-aminopyridine (3)
NH2CH2CH2Cl (5)
NH2CH2CH2Cl (5)
MEDG, reflux/4
MEDG, reflux/4
2f R = p-C6H4Cl (70)
2g R = p-C6H4Br (82)
10
11
12
13
14
15
16
MEDG, reflux/4
2h R = p-C6H4COOH (76)
2i R = p-C6H4NO2 (10)
2i R = p-C6H4NO2 (56)
MEDG, reflux/4
MEDG, 180/4, autoclave
MP, reflux/4
2j R = 2-C5H4N (11)
2j R = 2-C5H4N (11), 9 R = OC6H5 (63)
11 R = CH2CH2/Cl (44)
phenol, 180/1
MEDG, reflux/4
MEDG, 180/4, autoclave
11 R = CH2CH2/Cl (53)
S
S
NH2CH2CH2Cl
1
MEDG
N
N
N
N
N
N
CH2CH2Cl
Cl
2k
11
Scheme 4
Since substituted 4-aminoquinolines can be easily
obtained in reactions of chloroquinolines with alkyl-
amines in hot phenol via phenoxy derivative [14], we
tried to use the by-product, sulfide 9, in synthesis of
diquinothiazines 2. Although sulfide 9 was unreactive
towards selected alkyl-amine, butylamine, in MEDG, its
dihydrochloride (9 x 2HCl) gave 6-butyldiquinothiazine
2c in good yield, 73% (Scheme 5).
ronitrobenzene. 4-Chloro- and 4-bromonitrobenzene were
ineffective under these reaction conditions. In the case of
benzylation and nitrophenylation synthesis of diquino-
thiazines 2d and 2i was more effective than using the
annulation reactions.
Table 2. N-Alkylation and N-arylation reactions of 6H-
diquinothiazine 2H in DMF (20 oC/24 h)
No Alkylating or arylating agent Diquinothiazine 2 (yield, %)
S
S
C4H9NH2
MEDG
1
2
3
4
5
6
7
methyl iodide
butyl iodide
2a R = CH3 (64)
2c R = CH2CH2CH2CH3 (59)
2d R = CH2C6H5 (83)
N
N
N
N
H
N
H
OPh PhO
C4H9
2c
benzyl chloride
4-fluoronitrobenzene
ethyl iodide
2Cl
2i R = C6H4NO2 (86)
2l R = CH2CH3, (61)
9 * 2HCl
Scheme 5
allyl bromide
2m R = CH2CH=CH2 (68)
2n R = CH2COC6H5 (79)
phenacyl bromide
6-Substituted diquinothiazines were also obtained in the
thiazine hydrogen substitution in 6H-diquinothiazine 2H.
N-Alkylation reactions were carried out in DMF in the
presence of sodium hydride at room temperature with
selected alkyl halides (methyl, ethyl, butyl, allyl, benzyl
and phenacyl) to give diquinothiazines 2a, 2c, 2d and 2l-
2n with relatively good yield (59-83%, Scheme 6, Table
2). N-Arylation to give nitrophenyldiquinothiazine 2i was
succeeded in 86% in the case of phenylation with 4-fluo-
Physical and spectroscopic properties of diquino-
thiazines 2. The annulation rections of sulfide 1 and N-
alkylation reactions of diquinothiazine 2H were followed
by TLC analysis. All chromatograms of diquinothiazines
2 showed colour changes (from blue to yellow) during
irradiation with UV lamp unlike to chromatograms of
sulfides 1 and 8-10. Similar effect (orange colour for
diquinothiazine 2H and yellow colour for diquino-
thiazines 2a-2n) was observed when chromatograms of
diquinothiazines 2 were sprayed with a phenothiazine
detection mixture (sulfuric acid-water-ethanol 1:1:8) [15].
Only diquinothiazinium salt 11 gave a spot of intensive
yellow colour at once.
S
NaH, RX
2H
DMF
N
N
N
R
2a, 2c, 2d, 2i, 2l-2n
Scheme 6

546
M. Nowak, K. Pluta, K. Suwiꢀska and L. Straver
Vol 44
The 1H NMR spectra of the obtained diquinothiazines 2
is perfectly planar in configuration (the sum of the C-N3-
C bond angles is 360(4)°) and the C21-N3...S1 angle is
178.3(3)° which suggests the sp2 hybridization of the
nitrogen atom. The planar thiazine ring permits an
increase of the C2-N3-C12 and C3-S1-C13 bond angles in
comparison with the appropriate angles in diquinothiazine
2b. The phenyl ring plane bisects the pentacene ring
system with the angle between the phenyl ring plane and
the C2/C3/-C12/C13 plane of 78.3(1)°. The bisecting
conformation of the nitrophenyl group is also shown by
the torsion angles about the N(3)-C(21) bond: C(2)-N(3)-
C(21)-C(22) and C(2)-N(3)-C(21)-C(26) of -79.9(6)° and
97.9(6)°. The nitro group plane is tilted from the phenyl
ring plane by 3.5(5)°. It is worth noting that the phenyl
group plane in 10-(p-nitrophenyl)phenothiazine is
perpendicular to the bisecting plane of tricyclic ring
system as a result of resonance interactions between the
thiazine nitrogen atom and the phenyl carbon atom. As a
consequence of these interactions, the nitrophenyl
substituent is situated in an axial location and the Cphenyl-N
bond is shorter than usual (1.389 Å) [24]. The analogous
bond in diquinothiazine 2b (C21-N3) is significantly
longer, 1.443(6) Å. It seems that the electron-accepting
N1 and N2 nitrogen atoms in p-nitrophenyldiquino-
thiazine 2i prevents overlapping of the N3 lone pair and
the ꢀ-deficient p-nitrophenyl ring.
recorded in deuteriochloroform showed four multiplets
(two doublet-shaped with one ortho-coupling and two
triplet-shaped multiplets with two ortho-coupling, J = 7-
8.5 Hz) of an ABCD system of benzene ring protons and
a singlet of the pyridine ring protons (H12/H14).
Unquestionable assignment of the benzene protons
(H1/H11, H2/H10, H3/H9 and H4/H8) was based on
1
homonuclear NOE experiment and homonuclear H-1H
correlation (COSY) as described in reference [13] for
1
compounds 2a and 2b. All the H NMR spectra for
diquinothiazines 2 showed the spectral equivalency of the
left and right parts of the molecule. This result is evidence
that all these reactions ran without a cleavage of the C-S
bond and the Smiles rearrangement as we found for other
diquinolinyl sulfides [16-18]. Only diquinothiazinium salt
11 showed the spectral nonequivalency of both parts of
the molecule. Mass spectra of diquinothiazines 2 revealed
relatively high intensity of the molecular ions and some
fragmentary ions. In the case of compound 11 the
molecular ion was equal with diquinothiazinium cation
(m/z = 328).
All diquinothiazines 2 show promising potential anti-
psychotic, antidepressant, antihistaminic, antiasthmatic,
anticancer and sedative activity [19] and very lipophilic
character (logP = 4.13-6.85) [20].
X-ray study. There are only a few reports on the
crystal structure of heteropentacenes [12,13,18,21]. The
X-ray study of compounds 2b [21] and 2i confirmed their
triazathiapentacene structure and the C2v symmetry. In the
search of biologically active heterocycles, a series of 10-
arylphenothiazines were synthesized and X-ray structure
studied. The most interesting structural aspects (boat
conformation of the thiazine ring, a butterfly folding
around the N...S axis, location and rotation of the aryl
substituent and the N-aryl bond length) were concerned
with aryl substituents, especially substituted phenyls with
electron-donating and electron-accepting groups. These
studies indicated that the phenyl substituent can be in the
equatorial or axial location and the phenyl ring plane is
coplanar or perpendicular to the plane bisecting the
dihedral angle of the phenothiazine ring system depending
on steric and electronic interactions [2,22-25]. Whereas
X-ray analysis of phenyldiquinothiazine 2b showed
folding ring system with the central thiazine ring in boat
conformation [21], the analysis of p-nitrophenyl-
diquinothiazine 2i revealed planar thiazine ring. The
folding angle between the planes of the two halves of the
thiazine ring (i.e. C2/C3/S1/N3 and C12/C13/S1/N3) is
178.4(2)°. The displacements of S1 and N3 atoms from
the central C2/C3/C12/C13 was very small in comparison
with compound 2b (Table 3). The pentacyclic ring system
is a little twisted (Figure 1) with the angle between the
quinoline ring planes of 164.8(1)°. The nitrogen atom N3
Table 3. Comparison of geometrical features of diquinothiazines 2b and
2i
2b [21]
2i
Geometrical feature
C3/C13-S1 bond length/Å
1.750(3), 1.761(4)
1.395(40, 1.410(4)
1.752(5),
1.743(6)
1.412(7),
1.408(7)
1.443(6)
102.6(3)
125.7(4)
178.4(2)
C2/C12-N3 bond length/Å
C21-N3 bond length/Å
C3-S1-C13 angle/o
C2-N3-C12 angle/o
1.451(4)
100.1(2)
123.8(2)
149.4(1)
Angle between the halves of the
thiazine ring/o
Dihedral angle between the
quinoline moieties/o
159.5(1)
73.4(1)
164.8(1)
78.3(1)
Dihedral angle between the phenyl
ring and C2/C3/C12/C13 planes/o
Displacement of the S1 atom from
C2/C3/C12/C13 plane/ Å
Displacement of the N3 atom from
C2/C3/C12/C13 plane/ Å
0.481(1)
0.247(4)
-0.028(2)
- 0.007(4)
In the crystal the parallel stacking of pentacene rings is
observed (Figure 2). The distance between the r.m.s.
planes of the pentacene rings of two neighbouring
molecules in the stack is 3.777(8) Å. The nitrophenyl
substituents of the stacking molecules are also parallel
and the distance between the r.m.s. planes of nitrophenyl
is 2.739(7) Å. This is the first example of the N-
substituted diareno-1,4-thiazines, excluding some

May-Jun 2007
Synthesis of New Pentacyclic Diquinothiazines
547
Figure. 1. A view of compound 2i with atom numbering. Displacement ellipsoids are drawn at the 50% probability level.
Figure 2. A Stereoview of the unit cell along b direction. Hydrogen atoms are omitted for clearity.

548
M. Nowak, K. Pluta, K. Suwiꢀska and L. Straver
Vol 44
chloride (10 ml) was added very carefully drop by drop through
a condenser. The mixture was refluxed for 10 hours and the
progress of the reaction was monitored by TLC. After cooling,
the reaction was stirred with ice (20 g) and alkalized with
concentrated ammonia to pH~10. The resulting solid was
collected by filtration, washed with water, air-dried and purified
by column chromatography (silica gel, methylene chloride) to
give sulfide 1 (0.28 g, 78%); mp 198-199 °C (lit [27] 198-200
°C).
complexes with inorganic salts and organic compounds
[26], with the thiazine ring to be planar.
CONCLUSION
We report an efficient synthesis of novel triazathiapen-
tacenes being diquinothiazines 2 in the annulation reac-
tion as a thiazine ring closure of 2,2'-dichloro-3,3'-diqui-
nolinyl sulfide 1 with ammonia derivatives and primary
alkyl, alkylaryl, aryl and heteroaryl amines. 6H-Diquino-
thiazine 2H was transformed into 6-substituted diquino-
thiazines 2 via N-alkylation and N-arylation. The crucial
substrate 1 was obtained from other diazadithiapentacenes
3 and 4 via 1,4-dithiin ring opening and further transfor-
mations. X-ray analysis of p-nitrophenyldiquinothiazine
2i revealed unexpected planar thiazine ring.
6H-Diquinothiazine (2H).
A. Reaction with ammonium carbonate in MEDG. To a
solution of sulfide 1 (0.36 g, 1 mmole) in boiling MEDG (10 ml)
ammonium carbonate (0.48 g, 5 mmoles) was added portionally
during 4 hours. After cooling the reaction mixture was poured
into water (25 ml). The resulting solid was collected by
filtration, washed with water, air-dried and purified by column
chromatography (silica gel, chloroform-ethanol 10:1) to give:
6H-diquinothiazine (2H). This compound was obtained as
orange powder (0.03 g, 10%); mp > 300 °C; 1H NMR: ꢀ
(CDCl3) 7.38 (m, 2H, 2-H, 10-H), 7.54 (m, 2H, 1-H, 11-H), 7.59
(m, 2H, 3-H, 9-H), 7.71 (s, 2H, 12-H, 14-H), 7.82 (m, 2H, 4-H,
8-H); MS: m/z (EI) 301 (M+, 100), 269 (17.9, M-S), 257 (8.2,
M-CS). Anal. Calcd for C18H11N3S: C, 71.74; H, 3.68; N, 13.94.
Found: C, 71.57; H, 3.72; N, 13.68.
2,2'-diamino-3,3'-diquinolinyl sulfide (7). This compound
was obtained as yellow crystals (0.14 g, 44%); mp 218-220 °C;
1H NMR: ꢀ (CDCl3) 7.53 (m, 2H, 2 ꢀ 6-H), 7.70 (m, 2H, 2 ꢀ 7-
H), 7.76 (m, 2H, 2ꢀ 5-H), 8.03 (m, 2H, 2 ꢀ 8-H), 8.19 (s, 2H, 2
ꢀ 4-H); MS: m/z (EI) 318 (M+, 100), 301 (29.7, M-NH3). Anal.
Calcd for C18H14N4S: C, 67.90; H, 4.43; N, 17.60. Found: C,
67.58; H, 4.75; N, 17.27.
B. Reaction with ammonia in phenol. To a solution of
sulfide 1 (0.36 g, 1 mmole) in phenol (2 g) at 180 °C gaseous
ammonia was portionally during 1 hour. After cooling, water
was added and the phenol was removed by distillation. The
resulting solid was collected by filtration, washed with water,
air-dried and purified by column chromatography (silica gel,
chloroform-ethanol 10:1) to give: 6H-diquinothiazine (2H) (0.04
g, 13%); mp > 300 °C.
2,2'-diphenoxy-3,3'-diquinolinyl sulfide (9). This compound
was obtained as white crystals (0.18 g, 39%); mp 129-130 °C;
1H NMR: ꢀ (CDCl3) 7.19 (m, 4H, 2 ꢀ C6H2), 7.44 (m, 8H, 2 ꢀ 6-
H, 2 ꢀ C6H3), 7.60 (m, 2H, 2 ꢀ 7-H), 7.67 (m, 2H, 2 ꢀ 5-H), 7.75
(m, 2H, 2 ꢀ 8-H), 8.10 (s, 2H, 2 ꢀ 4-H); MS: m/z (EI) 472 (M+,
88.5), 379 (100, M-OPh). Anal. Calcd for C30H20N2O2S: C,
76.25; H, 4.27; N, 5.93. Found: C, 75.91; H, 4.43; N, 5.79.
C. Reaction with potassium carbonate in acetamide. To
acetamide (3.70 g, 60 mmoles) at 180 °C a mixture of sulfide 1
(0.36 g, 1 mmole) and potassium carbonate (0.56 g, 4 mmoles)
was added portionally during 10 minutes. The mixture was
stirred for 20 minutes. After cooling water (10 ml) was added
and the resulting solid was collected by filtration, washed with
water, air-dried and crystallized from DMF to give 6H-
diquinothiazine (2H) (0.17 g, 57%); mp > 300 °C.
EXPERIMENTAL
Melting points were determined in open capillary tubes on a
1
Boetius melting point apparatus and are uncorrected. The H
NMR spectra were recorded on a Varian Unity-Inova-300
spectrometer at 300 MHz in deuteriochloroform with
tetramethylsilane as the internal standard. Mass spectra (EI MS
and FAB MS in the m-nitrobenzyl alcohol matrix) were run on a
Finnigan MAT 95 spectrometer at 70 eV. The thin layer
chromatography were performed on silica gel 60 F254 (Merck
1.05735) with chloroform-ethanol (10:1 v/v) and on aluminum
oxide 60 F254 neutral (type E) (Merck 1.05581) with methylene
chloride as eluent.
Synthesis. Diquinodithiins 3 and 4 were obtained from 3-
bromo-2(1H)-quinolinethione or 2-chloro-3-bromoquinoline
according to described procedure [18].
2,2'-Dimethyl-3,3'-diquinolinyl sulfide (7).
A. from diquinodithiin (3). To a suspension of diquino-
dithiin (3) (0.32 g, 1 mmole) in dry DMSO (10 ml) at 70 °C was
added S-methylisothiouronium sulfate (0.21 g, 1.5 mmoles) and
lithium hydroxide (LiOH ꢀ H2O, 0.13 g, 3 mmoles). The
mixture was stirred for 30 min. After cooling the reaction
mixture was poured into 15% aqueous sodium hydroxide (30
ml). Possibly unreacted substrates were filtered off and the
filtrate was stirred with methyl iodide (0.1 ml, 1.6 mmoles). The
resulting solid was collected by filtration, washed with water,
air-dried and purified by column chromatography (silica gel,
methylene chloride) to give sulfide 7 (0.31 g, 82%); mp 188-189
°C (lit [18] 188-189 °C).
B. from diquinodithiin 4. To a suspension of diquinodithiin 4
(0.32 g, 1 mmole) in dry DMSO (10 ml) at 140 °C was added S-
methylisothiouronium sulfate (0.21 g, 1.5 mmoles) and lithium
hydroxide (LiOH ꢀ H2O, 0.13 g, 3 mmoles). The mixture was
stirred for 30 min. After cooling the reaction mixture was poured
into 15% aqueous sodium hydroxide (30 ml). Possibly unreacted
substrates were filtered off and the filtrate was stirred with methyl
iodide (0.1 ml, 1.6 mmoles). The resulting solid was collected by
filtration, washed with water, air-dried and purified by column
chromatography (silica gel, methylene chloride) to give sulfide 7
(0.21 g, 55%); mp 188-189 °C (lit [18] 188-189 °C).
6-Substituted diquinothiazines (2)
A. in the annulation reactions of sulfide 1 - general
procedure. To a solution of sulfide 1 (0.36 g, 1 mmole) in
MEDG (5 ml), boiling or at 180 °C in an autoclave or in phenol
(2 g, at 180 °C), or in boiling 1-methyl-2-pyrrolidinone (5 ml)
amine (3, 5 or 10 mmoles, Table 1) was added. The reaction
mixture was heated for 3 or 4 hours. After cooling the mixture
2,2'-Dichloro-3,3'-diquinolinyl sulfide (1). To a solution of
sulfide 7 (0.38 g, 1 mmole) in ethanol (10 ml) phosphoryl

May-Jun 2007
Synthesis of New Pentacyclic Diquinothiazines
549
was poured into water (25 ml). In the case of the phenol
procedure phenol was removed by steam distillation. The
resulting solid was collected by filtration, washed with water,
air-dried and purified by column chromatography (silica gel,
chloroform) to give diquinothiazines 2a, 2c-2j and sulfides 8-10
(Table 1).
6-(2'-Pyridyl)diquinothiazine (2j). This compound was
obtained as orange crystals; mp 194-195 °C; 1H NMR: ꢀ
(CDCl3) 7.26 (m, 2H, 2-H, 10-H), 7.39 (m, 4H, 3-H, 4-H, 8-H,
9-H), 7.49 (m, 4H, 1-H, 11-H, 3-Hpyridynyl, 5-Hpyridynyl), 7.74 (s,
2H, 12-H, 14-H) 7.99 (m, 1H, 4-Hpyridynyl), 8.79 (m, 1H, 6-
Hpyridynyl); MS: m/z (EI) 378 (M+, 85.0), 377 (100, M-1). Anal.
Calcd for C23H14N4S: C, 73.00; H, 3.73; N 14.80. Found: C,
72.85; H, 3.78; N, 14.42.
6-Methyldiquinothiazine (2a). This compound had mp 200-
201 °C (lit [13] 200-201 °C).
6-Butyldiquinothiazine (2c). This compound was obtained as
yellow crystals; mp 136-137 °C; 1H NMR: ꢀ (CDCl3) 1.07 (t, 3H, J
= 8.6 Hz, CH3), 1.57 (m, 2H, J = 8.6 Hz, CH2), 1.85 (m, 2H, J = 8.6
Hz, CH2), 4.67 (t, 2H, J = 8.6 Hz, CH2),7.28 (m, 2H, 2-H, 10-H),
7.51 (m, 4H, 1-H, 3-H, 9-H, 11-H), 7.66 (s, 2H, 12-H, 14-H), 7.76
(m, 2H, 4-H, 8-H); MS: m/z (EI) 357 (M+, 48.9), 328 (13.2, M-
C2H5), 301 (100, M-C4H8). Anal. Calcd for C22H19N3S: C, 73.92; H,
5.36; N, 11.75. Found: C, 73.64; H, 5.46; N, 11.47.
2,2'-Dibenzylamino-3,3'-diquinolinyl sulfide (10). This
compound was obtained as yellow crystals; mp 193-194 °C; H
1
NMR: ꢀ (CDCl3) 4.73 (d, 4H, J = 5.4 Hz, 2 ꢀ CH2), 5.70 (t, 2H,
J = 5.4 Hz, 2 ꢀ NH), 7.21 (m, 12H, 2 ꢀ 6-H, 2 ꢀ Ph), 7.48 (m,
2H, 2 ꢀ 5-H), 7.56 (m, 2H, 2 ꢀ 7-H), 7.73 (m, 2H, 2 ꢀ 8-H), 7.91
(s, 2H, 2 ꢀ H-4); MS: m/z (EI) 498 (M+, 55.3), 408 (48.7, M-
CH2Ph). Anal. Calcd for C32H26N4S: C, 77.08; H, 5.26; N,
11.24. Found: C, 76.89; H, 5.47; N, 10.92.
6-Benzyldiquinothiazine (2d). This compound was obtained
as yellow crystals; mp 144-145 °C; 1H NMR: ꢀ (CDCl3) 6.04 (S,
2H, CH2), 7.18 (m, 2H, o-Ph), 7.25 (m, 3H, 2-H, 10-H, p-Ph),
7.49 (m, 2H, 3-H, 9-H), 7.51 (m, 2H, 1-H, 11-H), 7.63 (m, 2H,
m-Ph), 7.66 (s, 2H, 12-H, 14-H), 7.73 (m, 2H, 4-H, 8-H); MS:
m/z (EI) 391 (M+, 100), 300 (44.3, M-Ph). Anal. Calcd for
C25H17N3S: C, 76.70; H, 4.38; N, 10.73. Found: C, 76.32; H,
4.29; N, 10.35.
5,6-Ethylenediquinothiazinium
chloride
(11).
This
1
compound was obtained as yellow powder; mp > 300 °C; H
NMR: ꢀ (CDCl3) 4.26 (t, 2H, J = 9.9 Hz, CH2), 4.95 (t, 2H, J =
9.9 Hz, CH2), 7.51-7.94 (m, 8H, 1-H, 2-H, 3-H, 4-H, 8-H, 9-H,
10-H, 11-H), 8.38 and 8.57 (2s, 2H, 12-H, 14-H); MS: m/z
(FAB) 328 (M-Cl, 21.3), 145 (100, m-nitrobenzyl alcohol).
Anal. Calcd for C20H14ClN3S: C, 66.02; H, 3.88; N, 11.55.
Found: C, 65.79; H, 3.91; N, 11.21.
6-(p-Tolyl)diquinothiazine (2e). This compound was
obtained as yellow crystals; mp 236-237 °C; 1H NMR: ꢀ
(CDCl3) 2.52 (s, 3H, CH3) 7.25 (m, 2H, 2-H, 10-H), 7.31 (m,
2H, o-C6H4), 7.38 (m, 2H, m-C6H4), 7.39 (m, 2H, 3-H, 9-H),
7.48 (m, 2H, 1-H, 11-H), 7.51 (m, 2H, 4-H, 8-H), 7.75 (s, 2H,
12-H, 14-H); MS: m/z (EI) 391 (M+, 60.4), 390 (100, M-1).
Anal. Calcd for C25H17N3S: C, 76.70; H, 4.38; N, 10.73. Found:
C, 76.48; H, 4.42; N, 10.42.
B. In the annulation reaction of sulfide 9 ꢀ 2HCl. A
solution of sulfide 9 ꢀ 2HCl (0.54 g, 1 mmole, obtained from
sulfide 9 and hydrochloric acid) and butylamine (0.30 ml, 3
mmoles) in MEDG (5 ml) was refluxed for 4 hours. Another
portion of butylamine (0.20 ml, 2 mmoles) was added and the
reaction mixture was refluxed for 2 hours. After cooling the
mixture was poured into water (25 ml). In the case of the phenol
procedure phenol was removed by steam distillation. The
resulting solid was collected by filtratino, washed with water,
air-dried and purified by column chromatography (silica gel,
chloroform) to give 6-butyldiquinothiazine (2c) (0.26 g, 73%).
C. In N-alkylation and N-arylation reactions - general
procedure. To a solution of 6H-diquinothiazine (2H) (0.30 g, 1
mmole) in dry DMF (10 ml) sodium hydride (0.24 g, 10
mmoles) was added. The reaction mixture was stirred for 1.5
hours at room temperature and then alkyl or aryl halide (3
mmoles, Table 2). The stirring was continued for 24 hours and
the mixture was poured into water (40 ml). The resulting solid
was collected by filtration, washed with water, air-dried and
purified by column chromatography (silica gel, chloroform) to
give 6-substituted diquinothiazines 2a, 2c, 2d, 2i and 2l-2n as
pale yellow crystals (Table 2):
6-(4'-Chlorophenyl)diquinothiazine (2f). This compound
1
was obtained as yellow crystals; mp 256-257 °C; H NMR: ꢀ
(CDCl3) 7.27 (m, 2H, 2-H, 10-H), 7.38 (m, 2H, o-C6H4), 7.43
(m, 2H, 3-H, 9-H), 7.48 (m, 2H, 1-H, 11-H), 7.53 (m, 2H, 4-H,
8-H), 7.54 (m, 2H, m-C6H4), 7.77 (s, 2H, 12-H, 14-H); MS: m/z
(EI) 411 (M+, 69.5), 413 (27.3, M+2), 410 (100, M-1). Anal.
Calcd for C24H14ClN3S: C, 69.98; H, 3.43; N, 10.20. Found: C,
69.63; H, 3.32; N, 10.02.
6-(4'-Bromophenyl)diquinothiazine (2g). This compound
1
was obtained as yellow crystals; mp 265-266 °C; H NMR: ꢀ
(CDCl3) 7.30 (m, 2H, 2-H, 10-H), 7.32 (m, 2H, o-C6H4), 7.43
(m, 2H, 3-H, 9-H), 7.49 (m, 2H, 1-H, 11-H), 7.53 (m, 2H, 4-H,
8-H), 7.54 (m, 2H, m-C6H4), 7.70 (s, 2H, 12-H, 14-H); MS: m/z
(EI) 455 (M+, 57.8), 457 (63.5, M+2), 456 (100, M+1). Anal.
Calcd for C24H14BrN3S: C, 63.17; H, 3.09; N, 9.21. Found: C,
62.92; H, 3.18; N, 8.90.
6-Ethyldiquinothiazine (2l). This compound was obtained as
1
yellow crystals; mp 180-181 °C; H NMR: ꢀ (CDCl3) 1.50 (t,
6-(4'-Carboxyphenyl)diquinothiazine (2h). This compound
was obtained as yellow crystals; mp 212-214 °C; H NMR: ꢀ
3H, J = 6.8 Hz, CH3), 4.47 (q, 2H, J = 6.8 Hz, CH2),7.29 (m, 2H,
2-H, 10-H), 7.52 (m, 4H, 1-H, 3-H, 9-H, 11-H), 7.66 (s, 2H, 12-
H, 14-H), 7.77 (m, 2H, 4-H, 8-H); MS: m/z (EI) 329 (M+, 47.4),
314 (22.2, M-CH3), 301 (100, M-C2H4), 300 (14.2, M-C2H5).
Anal. Calcd for C20H15N3S: C, 72.92; H, 4.59; N, 12.76. Found:
C, 72.68; H, 4.61; N, 12.67.
6-Allyldiquinothiazine (2m). This compound was obtained as
yellow crystals; mp 149-150 °C; 1H NMR: ꢀ (CDCl3) 5.22 (d, 1H,
J = 10.2 Hz, CH2=), 5.37 (d, 2H, J = 5.7 Hz, CH2), 5.55 (d, 1H, J =
18.6 Hz, CH2=), 6.23 (m, 1H, J = 5.7 Hz, CH=), 7.29 (m, 2H, 2-H,
10-H), 7.51 (m, 4H, 1-H, 3-H, 9-H, 11-H), 7.67 (s, 2H, 12-H, 14-
H), 7.76 (m, 2H, 4-H, 8-H); MS: m/z (EI) 341 (M+, 35.0), 326
(100, M-CH3), 300 (12.3, M-C3H5). Anal. Calcd for C21H15N3S: C,
73.87; H, 4.43; N, 12.31. Found: C, 73.50; H, 4.46; N, 11.99.
1
(CDCl3) 7.42 (m, 6H, 2-H, 10-H, C6H4), 7.51 (m, 4H, 1-H, 3-H,
9-H, 11-H), 7.59 (m, 2H, 4-H, 8-H), 7.77 (s, 2H, 12-H, 14-H);
MS: m/z (EI) 421 (M+, 1), 377 (61.1, M-CO2), 376 (100, M-
COOH). Anal. Calcd for C25H15N3O2S: C, 71.24; H, 3.59; N,
9.97. Found: C, 71.11; H, 3.70; N, 9.76.
6-(4'-Nitrophenyl)diquinothiazine (2i). This compound was
1
obtained as yellow crystals; mp > 300 °C; H NMR: ꢀ (CDCl3)
7.31 (m, 2H, 2-H, 10-H), 7.45 (m, 4H, 3-H, 4-H, 8-H, 9-H), 7.57
(m, 2H, 1-H, 11-H), 7.66 (m, 2H, o-C6H4), 7.82 (s, 2H, 12-H,
14-H) 8.45 (m, 2H, m-C6H4); MS: m/z (EI) 422 (M+, 100), 421
(90.3, M-1), 410 (100, M-1). Anal. Calcd for C24H14N4O2S: C,
68.23; H, 3.34; N, 13.26. Found: C, 68.01; H, 3.38; N, 12.94.

550
M. Nowak, K. Pluta, K. Suwiꢀska and L. Straver
Vol 44
[5] Marti, C.; Irurre, J.; Alvarez-Larena, A.; Piniella, J. F.;
Brillas, E.; Fajari, L.; Alemán, C.; Juliá, L. J. Org. Chem. 1994, 59,
6200.
[6] Engman, L.; Hellberg, J.; Ishaq, C.; Söderholm, S. J. Chem.
Soc., Perkin Trans. I 1988, 2095.
[7] Hellberg, J.; Pelcman, M. E. Tetrahedron Lett. 1994, 35,
1769.
[8] Ahmad, A. R.; Mehta, L. K.; Parrick, J. J. Chem. Soc., Perkin
Trans. I 1996, 2443.
6-Phenacyldiquinothiazine (2n). This compound was
1
obtained as yellow crystals; mp 82-83 °C; H NMR: ꢀ (CDCl3)
5.59 (s, 2H, CH2), 7.48 (s, 2H, 12-H, 14-H), 7.58 (m, 6H, 1-H,
2-H, 3-H, 9-H, 10-H, 11-H), 7.60 (m, 3H, 4-H, 8-H, p-Ph), 7.98
(m, 2H, C6H2), 8.15 (m, 2H, C6H2); MS: m/z (EI) 419 (M+,
31.2), 314 (42.2, M-COPh), 105 (100, PhCO+). Anal. Calcd for
C26H17N3OS: C, 74.44; H, 4.08; N, 10.02. Found C, 74.19; H,
4.32; N, 9.84.
X-Ray analysis. Single crystals of 6-(4'-nitrophenyl)diquin-
othiazine 2i were obtain by recrystallization from DMF. The
[9] Boros, E. E.; Harfenist, M. J. Org. Chem. 1998, 63, 10045.
[10] Anthony, J. E.; Brooks, J. S.; Eaton, D. L., Parkin, S. R. J.
Am. Chem. Soc. 2001, 123, 9482.
[11] Yoshida, S.; Nozawa, K.; Sato, N.; Uchida, T. Bull. Chem.
Soc. Jpn. 1994, 67, 2017.
[12] Miao, Q.; Nquyen, T.-Q.; Someya, T.; Blanchet, G. B.;
Nuckolls, C. J. Am. Chem. Soc. 2003, 125, 10284.
[13] Nowak, M.; Pluta, K.; Suwiꢀska, K. New J. Chem. 2002, 26,
1216.
[14] Smalley, R. K. In The Chemistry of Heterocyclic Compounds,
vol. 32, Quinolines, Part 1, Jones, G. Ed, John Wiley and Sons, London,
1997, p 551.
[15] Stahl, E. Thin-Layer Chromatography, Springer, Berlin,
1969, p 508.
[16] Pluta, K. J. Heterocycl. Chem. 1992, 29, 1599.
[17] Pluta, K. J. Heterocycl. Chem., 1995, 32, 1245.
[18] Nowak, M.; Pluta, K.; Kloc, C.; Siegrist, T. Heterocycles
2003, 60, 2045.
[19] PASS (Prediction of Activity Spectra for Substance)
http://www.ibmh.msk.su/PASS.
[20] Nowak, M.; Pluta, K. J. Planar Chromatogr. 2006, 19, 157.
[21] Pluta, K.; Nowak, M.; Suwiꢀska, K. J.Chem. Crystallogr.
2000, 30, 479.
intensity data were collected on
a Bruker KappaApexII
diffractometer with graphite-monochromated CuKꢀ radiation
(ꢁ = 1.54178 Å). The structures were solved by direct methods
(SHELXS-97) [28] and refined on F2 by full-matrix least-
squares (SHELXL-97) [29]. All non-hydrogen atoms were
refined anisotropically, hydrogen atoms were 'riding' on their
carbon atoms (dC–H = 0.93 Å, Uiso = 1.2Ueq of the attached C
atom.
Crystal data for 2i: C24H14N4O2S, M = 422.45, translucent
needle, 0.25 ꢂ 0.08 ꢂ 0.04 mm, monoclinic, space group P21/c
(No. 14), a = 14.997(1), b = 5.1898(4), c = 23.951(2) Å, ꢁ =
97.194(6)°, V = 1849.5(2) Å3, Z = 4, Dc = 1.517 g/cm3, F000
872, T = 100(2)K, μ( CuKꢀ) = 1.825 mm-1.
=
16659 reflections collected (2ꢂmax = 117.6º), 2537 unique (Rint
= 0.125). Final GooF = 1.01, R = 0.089, wR = 0.212, R indices
based on 1564 reflections with I >2ꢃ(I), 281 parameters. Lp and
absorption corrections applied but no correction for absorption.
CIF file deposited with Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (No
292797).
[22] Jovanovic, M. V.; Biehl, E. R.; de Meester, P.; Chu, S. S. C.
J. Heterocycl. Chem. 1984, 21, 885.
[23] Jovanovic, M. V.; Biehl, E. R.; de Meester, P.; Chu, S. S. C.
J. Heterocycl. Chem. 1984, 21, 1425.
[24] Jovanovic, M. V.; Biehl, E. R.; de Meester, P.; Chu, S. S. C.
J. Heterocycl. Chem. 1984, 21, 1793.
REFERENCES
[1] Part XCIV in the series of Azinyl Sulfides.
[2] Gupta, R. R.; Kumar, M.; In Phenothiazines and 1,4-
Benzothiazines – Chemical and Biological Aspects, Gupta, R. R. Ed,
Elsevier, Amsterdam, 1988, pp 1-161.
[3] Pluta, K. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 126,
145.
[25] de Meester, P.; Chu, S. S. C.; Acta Cryst. Sect. C 1986, 42,
877.
[26] Cambridge Crystallographic Database, version 5.26, (2004).
[27] Dreikorn, B. A.; Elsasser, F. E.; Jourdan, G. P. J. Org. Chem.
1979, 44, 877.
[28] Sheldrick, G. M. Acta Cryst., Sect. A 1990, 46, 467.
[29] Sheldrick, G. M. SHELXL-97. Program for the Refinement
of Crystal Structures. Univ. of Goettingen, Germany, 1997.
[4] Pluta, K.; Maꢁlankiewicz, A.; Szmielew, M. Phosphorus,
Sulfur Silicon Relat. Elem. 2000, 159, 79.