Diastereoselective synthesis of (Z)-6-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H, 6H)-diones

Article abstract of DOI:10.1002/jhet.2008

Two efficient and diastereoselective procedures for the synthesis of (Z)-6-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3,3a,9,9a-tetrahydroimidazo[4,5-e] thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-diones by aldol-crotonic condensation of 1,3-dimethyl-3a,9a-diphe

Full text of DOI:10.1002/jhet.2008

July 2014
Diastereoselective Synthesis of (Z)-6-(2-Oxo-1,2-dihydro-3H-indol-3-
ylidene)-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,
4-triazin-2,7(1H,6H)-diones
921
*
Galina A. Gazieva, Ekaterina A. Shishkova, Ludmila B. Kulikova, Natal’ya G. Kolotyrkina,
Natal’ya V. Sigay, and Angelina N. Kravchenko
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991, Russian Federation
*
E-mail: gaz@ioc.ac.ru
Received December 26, 2012
DOI 10.1002/jhet.2008
Published online 9 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
Two efficient and diastereoselective procedures for the synthesis of (Z)-6-(2-oxo-1,2-dihydro-3H-indol-
3-ylidene)-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-diones by aldol-crotonic
condensation of 1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-
2,7(1H,6H)-dione with isatins under acidic or basic catalysis are reported. Isomerization in (Z)-7-(1-allyl-
2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-dimethyl-3a,9a-diphenyl-1,3a,4,9a-tetrahydroimidazo[4,5-e]
thiazolo[2,3-c]-1,2,4-triazin-2,8(3H,7H)-dione was observed under basic conditions.
J. Heterocyclic Chem., 51, 921 (2014).
INTRODUCTION
(1H,6H)-diones 3a–p through an aldol-crotonic condensation
of 1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo
[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione 1 with
isatins 2a–p under acidic or basic catalysis.
Indole moiety is a common and important feature of
variety of natural products and medicinal agents [1,2].
Furthermore, isatin (1H-indole-2,3-dione) derivatives have
been shown to possess a broad spectrum of biological
activities including antiviral, antitumor, antiangiogenic,
antibacterial, antifungal, anticonvulsant, and anxyolytic
effects [1–3]. On the other hand, thiazolo[3,2-b]-1,2,4-tri-
azines or [2,3-c]-1,2,4-triazines exhibit antidepressant [4],
anti-HIV, and anticancer properties [5]. One of the
approaches to combining of pharmacophore fragments in
the molecule is aldol-crotonic condensation of appropriate
carbonyl and active methylene compounds. For example,
condensation of various thiazolidinones with aldehydes
and ketones was carried out in acetic acid and acetic
anhydride, as well as in ethanol, methanol or toluene using
as a catalyst acids, sodium (potassium) acetate, KOH,
piperidine, and other bases [6–12].
Recently, we started to study aldol-crotonic condensation of
1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo
[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione 1 with
isatin 2a and N-alkylisatins 2b–f [12]. Condensation products,
namely, (Z)-1,3-dimethyl-6-(2-oxo-1,2-dihydro-3H-indol-
3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo
[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-diones
3a–f were prepared in 74–89% yields by refluxing reactants
in acetic acid for 2.5 h (Scheme 1) [12].
RESULTS AND DISCUSSION
Heating equimolar amounts of compound 1 with
N-alkylisatins 2g–j in acetic acid under reflux for 2.5 h
(method A) resulted in appropriate oxoindole derivatives
3g–j in 61–78% yields (Scheme 2, Table 1). However,
when functional substituted isatins 2k–p were allowed
to react with compound 1, the corresponding products
3k–p were obtained only in 10–20% yields. Therefore, the
reaction of imidazothiazolotriazine 1 with isatins 2 under
basic catalysis was studied. Boiling isatins 2a(f,k), com-
pound 1, and sodium acetate in ethanol did not lead to target
oxoindole derivatives 3a(f,k) in satisfactory yields. The
better yields of compounds 3a,f,k were achieved in boiling
methanol with 0.05 mL 40% aqueous KOH (method B).
The wide range of isatins (2a–p) reacted efficiently with
imidazothiazolotriazine 1 under the basic conditions
(40% KOH) to afford the corresponding products 3a–p in
55–67% yields (Scheme 2, Table 1).
1
In the H NMR spectra of the reaction products 3g,h,k,
p, the signals for the protons of the minor isomeric
products 4g,h,k,p were also observed in some cases when
the reaction time was 15–45 min (Scheme 2). However, the
total yield of isomers 3g,h,k,p and 4g,h,k,p was low, and
the starting compounds have still remained in the reaction
mixtures in this cases. Increase of the reaction time up
We continued the studies and report herein two simple
methods for the synthesis of (Z)-1,3-dimethyl-6-(2-oxo-1,2-
dihydro-3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-
tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7
© 2013 HeteroCorporation

922
G. A. Gazieva, E. A. Shishkova, L. B. Kulikova, N. G. Kolotyrkina, N. V. Sigay, and A. N. Kravchenko Vol 51
Scheme 1
Scheme 2
Table 1
Synthesis of oxoindolylidene derivatives 3.
Yield of 3/%
Entry
Substrate
R1
R2
Product
Method A
Method B
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
H
Me
i-Pr
n-Bu
Bn
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
86 [12]
89 [12]
78 [12]
82 [12]
74 [12]
82 [12]
78
71
61
64
11
61
63
63
65
62
66
59
67
62
63
66
61
61
56
63
55
(CH2)2 Ph
Et
CH2C6H4Cl-4
CH2C6H4Br-3
CH2C6H4Br-3
All
CH2CꢀCH
CH2COOEt
CH2CONH2
CH(Me)COOMe
CH(Me)COOEt
9
10
11
12
13
14
15
16
12
20
10
17
15
to 1–2 h led to enhancement of the yield of compounds 3g,
h,k,p (Table 1), but isomers 4 disappeared. Changing con-
centration of reactants and reaction time, we succeed in
obtaining (Z)-7-(1-allyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-
1,3-dimethyl-3a,9a-diphenyl-1,3a,4,9a-tetrahydroimidazo
[4,5-e]thiazolo[2,3-c]-1,2,4-triazin-2,8(3H,7H)-dione 4k
in 55% yield. We failed to prepare other isomers 4g,h,p
in their pure state.
Probably, in the reaction conditions, reversible opening of
thiazolidine cycle takes place. Quickly formed isomer 4
undergoes again rearrangement into more thermodynamically
stable isomer 3 with the lapse of time.
COSY, NOESY, HMBC, and HSQC methods. It is to be
mentioned that the H NMR spectra of compounds 3a–p
1
display a strong downfield shift of the indole H-40 proton
signals (8.84–8.91 ppm), which is characteristic of
proximity of the carbonyl group C(7)═O. Earlier, this fact
was proved by X-ray diffraction analysis of compounds
3a,f [12]. The 1H NMR spectra of isomers 4 display
a downfield shift of the indole H-40 proton signals
1
(8.50–8.58 ppm) in a less degree. In the H NMR spectra
of compounds 4, the NH protons resonate at downfield in
comparison with the NH protons of compounds 3.
Chemical shifts of protons N(1(3))-CH3 differ noticeably
for compounds 3 (two singlets at 2.63–2.65 and
2.64–2.66 ppm) and 4 (two singlets at 2.62–2.63 and
2.95ppm ).
The structures of isomers 3a–p and 4k were established
1
by HRMS, H NMR, and 13C NMR spectra data. The
signals in the spectra were assigned using highly sensitive
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis of (Z)-6-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)-3,3a,9,
923
9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-diones
General procedure for the synthesis of (Z)-1,3-dimethyl-6-(2-
oxo-1,2-dihydro-3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-
tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-
The structure of compound 4k was also proved on the
1
bases of H–{15N} HMBC spectrum and 15N CP MAS
spectrum data by comparison with quantum-chemical cal-
culation results (chemical shifts of bridgehead sp3-nitrogen
atom N(9) and sp2-nitrogen atom N(5) for compound 4k or
N(4) for compound 3k differed approximately on 100 ppm
[13]). The 1H–{15N} HMBC spectrum of compound
4k exhibited weak cross-peak between sp3-nitrogen atom
N(9) and N(1)–CH3 group protons (Fig. 1).
In summary, two efficient and diastereoselective procedures
for the synthesis of (Z)-1,3-dimethyl-6-(2-oxo-1,2-dihydro-
3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo
[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-diones
3a–p are designed. N-Alkylderivatives 3a–d,g arised in the
best yields (78–89%) by condensation of 1,3-dimethyl-3a,9a-
diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-
1,2,4-triazin-2,7(1H,6H)-dione 1 with N-alkylisatins 2a–d,
g in boiling acetic acid, functional substituted products
3k–p are obtained in 55–66% yields by condensation
of compound 1 with isatins 2k–p in boiling methanol
with 40% aqueous КОН, and N-arylalkylderivatives 3e,f,
h–j are formed in 65–71% yields under both acidic and
basic catalysis.
diones (3a-p).
Method A. A solution (or suspension) of
thiazolotriazine 1 (0.39g, 1 mmol) and appropriate isatins 2a–p
(1mmol) in 10 mL of glacial AcOH was refluxed for 2.5h.
After cooling, the precipitate of 3a–p was filtered off, washed
with AcOH and water, and recrystallized from ethyl acetate–
isopropanol (3:2) if necessary.
Method B. To a solution (or suspension) of thiazolotriazine 1
(0.39 g, 1 mmol) and appropriate isatins 2a–p (1 mmol) in
20 mL of refluxing MeOH, 0.05 mL of 40% aqueous KOH was
added. The reaction mixture was stirred under reflux for 1–2 h
and left to cool overnight. The separated solid products 3a–p
were filtered off and recrystallized from ethyl acetate–isopropanol
(3:2) if necessary.
(Z)-1,3-Dimethyl-6-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-
3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-
1,2,4-triazine-2,7(1H,6H)-dione (3a).
This compound was
obtained as red solid in 86% [12] (method A) or 61% (method B)
yield, mp 317–321ꢁC (MeOH) (Lit. [12] 239–241ꢁC (AcOH)); 1H
NMR spectra data are consistent with the literature values [12].
13C NMR: d 25.31 (NCH3), 26.00 (NCH3), 79.82 (C-9a), 81.78
(C-3a), 110.48 (indole C-70), 120.10, 122.00, 123.84, 126.26,
127.36, 127.66, 127.87, 128.00, 128.25, 132.00, 133.99, 134.81,
143.27 (indole C-70a), 149.20 (C═N), 159.15 (C═O), 159.73
(C═O), 168.58 (indole C═O).
(Z)-1,3-Dimethyl-6-(1-methyl-2-oxo-1,2-dihydro-3H-indol-3-
ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]
thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3b). This compound
was obtained as orange solid in 89% [12] (method A)
or 63% (method B) yield, mp 342–345ꢁC (MeOH) (Lit. [12]
EXPERIMENTAL
Melting points (uncorrected) were determined on a Kofler
melting point apparatus (VEB Wagetechnik Rapido, Radebeul,
Germany). HRMS were measured on a Bruker micrOTOF II
instrument using ESI [14]. The measurements were carried
out in a positive ion mode (interface capillary voltage,
4500 V) or in a negative ion mode (3200 V), mass range is from
m/z 50 to 3000 Da, and external or internal calibration was
carried out with Electrospray Calibrant Solution (Fluka). A
syringe injection was used for solutions in acetonitrile or
methanol (flow rate 3 mL/min). Nitrogen was applied as a dry
1
248–250ꢁC (AcOH)); H NMR spectra data are consistent with
the literature values [12]. 13C NMR: d 25.35 (NCH3), 26.02
(NCH3), 26.39 (NCH3), 79.82 (C-9a), 81.80 (C-3a), 109.28
(indole C-70), 119.38, 122.54, 124.96, 126.27, 127.37, 127.49,
127.66, 127.90, 128.02, 128.26, 130.02, 131.89, 133.98,
134.79, 144.25 (indole C-70a), 149.03 (C═N), 159.14 (C═O),
159.58 (C═O), 167.03 (indole C═O).
(Z)-6-(1-Isopropyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,
gas; interface temperature was set at 180ꢁC. H NMR and 13C
1
3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]
thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3c). This compound
was obtained as orange solid 78% [12] (method A) or 63% (method B)
yield, mp 290–293ꢁC (MeOH) (Lit. [12] 310–312ꢁC (AcOH));
1H NMR spectra data are consistent with the literature values
[12]. 13C NMR: d 19.14 (CH3), 19.20 (CH3), 25.31 (NCH3),
26.02 (NCH3), 44.28 (NCH), 79.84 (C-9a), 81.87 (C-3a), 110.21
(indole C-70), 119.72, 122.18, 125.18, 126.29, 127.36, 127.67,
127.72, 127.90, 128.00, 128.26, 129.98, 131.83, 134.00, 134.77,
142.95 (indole C-70a), 149.12 (C═N), 159.14 (C═O), 159.59
(C═O), 166.82 (indole C═O).
NMR spectra were recorded on a Bruker AM300 spectrometer
operating at 300.13 and 75.5 MHz, respectively, using
DMSO-d6 as solvent. Chemical shifts (d) are given in ppm from
TMS as internal standard.
Starting materials.
1,3-Dimethyl-3a,9a-diphenyl-3,3a,9,9a-
tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-
dione (1) was synthesized by the reaction of 5,7-dimethyl-4a,
7a-diphenylperhydroimidazo[4,5-e]-1,2,4-triazin-3,6-dione with
bromoacetic acid (Scheme 3) [15]. Isatins (2b–p) were
prepared by N-alkylation of isatin 2a [16–18].
Scheme 3
Figure 1. Structures of isomers 3k and 4k.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

924
G. A. Gazieva, E. A. Shishkova, L. B. Kulikova, N. G. Kolotyrkina, N. V. Sigay, and A. N. Kravchenko Vol 51
(Z)-6-(1-Butyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-
dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]
thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3d). This
(d, J = 7.2 Hz, 2H, phenyl), 7.06–7.18 (m, 8H, phenyl, indole),
7.37–7.44 (m, 5H, indole H-60, 4-ClC6H4), 7.87 (s, 1H, NH), 8.91
(d, J = 7.8 Hz, 1H, indole H-40); 13C NMR: d 25.32 (N(1)CH3),
26.03 (N(3)CH3), 42.42 (NCH2), 79.85 (C-9a), 81.92 (C-3a),
109.70 (indole C-70), 119.63, 122.76, 124.60, 126.29, 127.35,
127.65, 127.91, 127.98, 128.25, 128.68, 129.18, 130.90, 131.78,
132.23 (C-Cl), 133.95, 134.73, 134.96, 143.92 (indole C-70a),
148.87 (C═N), 159.14 (C(7)═O), 159.48 (C(2)═O), 167.27
(indole C═O); HRMS-ESI: m/z [M+ H] Anal. Calcd for
compound was obtained as orange solid 82% [12] (method A)
or 65% (method B) yield, mp 335–338ꢁC (MeOH) (Lit. [12]
1
338–340ꢁC (AcOH)); H NMR spectra data are consistent with
the literature values [12]. 13C NMR: d 13.51 (CH3), 19.45
(CH2), 25.28 (NCH3), 25.98 (NCH3), 29.05 (CH2), 43.05
(NCH2), 79.80 (C-9a), 81.82 (C-3a), 109.39 (indole C-70),
119.46, 122.39, 124.84, 126.25, 127.31, 127.63, 127.85,
127.96, 128.21, 130.43, 131.85, 133.97, 134.75, 143.48
(indole C-70a), 148.96 (C═N), 159.09 (C═O), 159.45 (C═O),
C35H27ClN6O3S: 647.1627; found: 647.1625.
(Z)-6-(1-(3-Bromobenzyl)-2-oxo-1,2-dihydro-3H-indol-3-
ylidene)-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo
[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3i). This compound
was obtained as red-orange solid in 61% (method A) or 62%
167.01 (indole C═O).
(Z)-6-(1-Benzyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-
dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]
1
(method B) yield, mp 265–267ꢁC; H NMR: d 2.64 (s, 3H, N
(3)CH3), 2.65 (s, 3H, N(1)CH3), 5.09 (dd, J = 23.1 Hz,
J = 16.2 Hz, 2H, NCH2), 6.76 (d, J = 7.0 Hz, 2H, phenyl), 6.84
(d, J = 7.1 Hz, 2H, phenyl), 7.05–7.18 (m, 8H, phenyl, indole),
7.29–7.34 (m, 2H, 3-BrC6H4), 7.40–7.51 (m, 2H, indole H-60,
3-BrC6H4), 7.59 (s, 1H, 3-BrC6H4 H-200), 7.84 (s, 1H, NH),
8.91 (d, J = 7.8 Hz, 1H, indole H-40); 13C NMR: d 25.49
(NCH3), 26.20 (NCH3), 42.64 (NCH2), 80.02 (C-9a), 82.10 (C-3a),
109.86 (indole C-70), 119.85, 122.09, 122.98, 124.78, 126.45,
127.53, 127.82, 128.16, 128.44, 130.16, 130.71, 131.09, 132.00,
134.14, 134.93, 138.95, 143.10 (indole C-70a), 149.02 (C═N),
159.30 (C═O), 159.67 (C═O), 167.52 (indole C═O); HRMS-
ESI: m/z [M + H] Anal. Calcd for C35H27BrN6O3S: 693.1103;
thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3e).
This
compound was obtained as orange solid 74% [12] (method A)
or 62% (method B) yield, mp 218–221ꢁC (MeOH) (Lit. [12]
1
208–210ꢁC (AcOH)); H NMR spectra data are consistent with
the literature values [12]. 13C NMR: d 25.28 (NCH3), 25.99
(NCH3), 43.06 (NCH2), 79.81 (C-9a), 81.88 (C-3a), 109.75
(indole C-70), 119.58, 122.66, 126.26, 127.21, 127.31, 127.54,
127.62, 127.95, 128.22, 128.67, 131.73, 133.95, 134.73,
135.89, 143.11 (indole C-70a), 148.85 (C═N), 159.09 (C═O),
159.47 (C═O), 167.23 (indole C═O).
(Z)-1,3-Dimethyl-6-(2-oxo-1-phenethyl-1,2-dihydro-3H-indol-
3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]
thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3f). This
compound was obtained as orange solid 82% [12] (method A)
or 66% (method B) yield, mp 296–298.5ꢁC (MeOH) (Lit. [12]
found: 693.1105.
(Z)-6-(5-Bromo-1-(3-bromobenzyl)-2-oxo-1,2-dihydro-3H-indol-
3-ylidene)-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo
[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3j). This
compound was obtained as yellow-orange solid in 64% (method
1
325–327ꢁC (AcOH)); H NMR spectra data are consistent with
the literature values [12]. 13C NMR: d 25.35 (NCH3), 26.03
(NCH3), 33.00 (CH2), 41.26 (NCH2), 79.84 (C-9a), 81.84 (C-3a),
109.49 (indole C-70), 119.38, 122.42, 124.76, 126.28, 126.46,
127.20, 127.36, 127.52, 127.67, 127.90, 128.01, 128.27, 128.38,
128.81, 130.15, 131.84, 133.98, 134.78, 138.10, 143.33
(indole C-70a), 149.01 (C═N), 159.15 (C═O), 159.54 (C═O),
1
A) or 63% (method B) yield, mp 281–283ꢁC; H NMR: d 2.65
(s, 6H, 2NCH3), 5.09 (dd, J = 22.8Hz, J = 16.0 Hz, 2H, NCH2),
6.76 (d, J= 6.8 Hz, 2H, phenyl), 6.84 (d, J= 6.9 Hz, 2H, phenyl),
7.06–7.17 (m, 7H, phenyl, indole H-70), 7.33 (br.s, 2H, 3-BrC6H4),
7.50 (br.s, 1H, 3-BrC6H4), 7.58 (s, 1H, 3-BrC6H4 H-2”), 7.61
(t, J= 8.9 Hz, 1H, indole H-60), 7.99 (s, 1H, NH), 9.11 (s, 1H, indole
H-40); 13C NMR: d 25.55 (NCH3), 26.23 (NCH3), 42.72 (NCH2),
80.01 (C-9a), 82.37 (C-3a), 111.74 (indole C-70), 114.69, 121.59,
122.13, 123.42, 126.40, 126.51, 127.54, 127.80, 128.13, 128.46,
129.99, 130.14, 130.77, 131.08, 133.26, 133.93, 134.04, 134.81,
138.63, 142.11 (indole C-70a), 148.56 (C═N), 159.29 (C═O),
159.51 (C═O), 167.16 (indole C═O); HRMS-ESI: m/z [M + H]
166.91 (indole C═O).
(Z)-6-(1-Ethyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-
dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]
thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3g). This compound
was obtained as orange solid in 78% (method A) or 59%
(method B) yield, mp 322–324ꢁC; 1H NMR:
d 1.22
(t, J = 6.9 Hz, 3H, CH3), 2.64 (s, 3H, N(3)CH3), 2.65 (s, 3H,
N(1)CH3), 3.86 (q, J = 6.9 Hz, 2H, NCH2), 6.76 (d, J = 7.2 Hz,
2H, phenyl), 6.83 (d, J = 7.3 Hz, 2H, phenyl), 7.05–7.24
(m, 8H, phenyl, indole), 7.48 (t, J = 7.7 Hz, 1H, indole H-60),
7.82 (s, 1H, NH), 8.89 (d, J = 7.9 Hz, 1H, indole H-40); 13C
NMR: d 12.60 (CH3), 25.30 (NCH3), 25.99 (NCH3), 34.58
(NCH2), 79.81 (C-9a), 81.83 (C-3a), 109.24 (indole C-70),
119.53, 122.40, 124.93, 126.25, 127.32, 127.63, 127.86,
127.96, 128.22, 130.09, 131.88, 133.96, 134.75, 143.13 (indole
C-70a), 148.97 (C═N), 159.10 (C═O), 159.52 (C═O), 166.66
(indole C═O); HRMS-ESI: m/z [M+ H] Anal. Calcd for
Anal. Calcd for C35H26Br2N6O3S: 771.0209; found: 771.0208.
(Z)-6-(1-Allyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-
dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]
thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3k). This compound
was obtained as orange solid in 11% (method A) or 66%
(method B) yield, mp 321–323ꢁC; 1H NMR: d 2.64 (s, 3H, N(3)
CH3), 2.66 (s, 3H, N(1)CH3), 4.49 (d, J = 4.1 Hz, 2H, NCH2),
5.19 (m, 2H, CH2), 5.87–5.96 (m, 1H, CH), 6.77 (d, J = 7.2 Hz,
2H, phenyl), 6.84 (d, J = 7.3 Hz, 2H, phenyl), 7.06–7.20 (m, 8H,
phenyl, indole), 7.47 (t, J = 7.6 Hz, 1H, indole H-60), 7.84 (s, 1H,
NH), 8.91 (d, J = 7.8 Hz, 1H, indole H-40); 13C NMR:
d 25.31 (NCH3), 26.00 (NCH3), 41.90 (NCH2), 79.81 (C-9a),
81.84 (C-3a), 109.74 (indole C-70), 117.16 (allyl═CH2), 119.49,
122.56, 124.71, 126.26, 127.34, 127.52, 127.64, 127.98, 128.25,
130.44, 131.56, 131.78, 133.95, 134.74, 143.25 (indole C-70a),
148.92 (C═N), 159.11 (C═O), 159.52 (C═O), 166.84 (indole
C═O); HRMS-ESI: m/z [M + H] Anal. Calcd for C31H26N6O3S:
563.1860; found: 563.1848.
C30H26N6O3S: 551.1854; found: 551.1860.
(Z)-6-(1-(4-Chlorobenzyl)-2-oxo-1,2-dihydro-3H-indol-3-
ylidene)-1,3-dimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo
[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3h).
This compound was obtained as red-orange solid in 71% (method
1
A) or 67% (method B) yield, mp 320–322ꢁC; H NMR: d 2.64
(s, 3H, N(3)CH3), 2.65 (s, 3H, N(1)CH3), 5.08 (dd, J = 19.4Hz,
J = 16.2Hz, 2H, NCH2), 6.76 (d, J = 6.9 Hz, 2H, phenyl), 6.84
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis of (Z)-6-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)-3,3a,9,
925
9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-diones
(Z)-1,3-Dimethyl-6-(2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydro-3H-
122.72, 124.22, 126.28, 127.33, 127.64, 127.75, 127.89, 127.96,
128.24, 131.14, 131.84, 133.95, 134.70, 142.31 (indole C-70a),
148.71 (C═N), 159.10 (C═O), 159.38 (C═O), 166.79, 169.96
(indole C═O C═O , ether C═O); HRMS-ESI: m/z [M + H] Anal.
Calcd for C32H28N6O5S: 609.1915; found: 609.1914.
indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo
[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-2,7(1H,6H)-dione (3l).
This compound was obtained as orange solid in 12% (method A) or
61% (method B) yield, mp 304–307ꢁC; 1H NMR: d 2.64 (s, 3H, N
(3)CH3), 2.65 (s, 3H, N(1)CH3), 3.32 (s, 1H, C ꢀ H), 4.73 (s, 2H,
NCH2), 6.77 (d, J = 6.9 Hz, 2H, phenyl), 6.84 (d, J = 7.0 Hz, 2H,
phenyl), 7.09-7.30 (m, 8H, phenyl, indole), 7.54 (t, J = 7.7 Hz, 1H,
indole H-60), 7.85 (s, 1H, NH), 8.92 (d, J = 7.7 Hz, 1H, indole
H-40); 13C NMR: d 25.37 (NCH3), 26.04 (NCH3), 29.26
(NCH2), 74.81 (CꢀCH), 77.58 (CꢀCH), 79.83 (C-9a), 81.92
(C-3a), 109.85 (indole C-70), 119.58, 123.00, 124.29, 126.29,
127.39, 127.67, 128.03, 128.29, 131.20, 131.84, 133.96, 134.72,
142.22 (indole C-70a), 148.78 (C═N), 159.15 (C═O), 159.43
(C═O), 166.40 (indole C═O); HRMS-ESI: m/z [M + Na] Anal.
Calcd for C31H24N6O3S: 583.1523; found: 583.1520.
(Z)-Ethyl 2-(3-(1,3-dimethyl-2,7-dioxo-3a,9a-diphenyl-1,2,3,3a,
9,9a-hexahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-6(7H)-
ylidene)-2-oxo-1,2-dihydro-3H-indolyl-1-)propanoate (3p). This
compound was obtained as red-orange powder in 15% (method A)
or 55% (method B) yield, mp 263–266ꢁC; 1H NMR: d 1.15
(t, J = 6.9 Hz, 3H, CH3), 1.60 (d, J = 7.0 Hz, 3H, CH3), 2.64
(s, 3H, N(3)CH3), 2.65 (s, 3H, N(1)CH3), 4.16 (q, J = 6.9 Hz, 2H,
OCH2), 5.33 (q, J = 7.0 Hz, 1H, NCH), 6.76 (d, J = 7.1 Hz, 2H,
phenyl), 6.83 (d, J = 7.1 Hz, 2H, phenyl), 7.05–7.23 (m, 8H,
phenyl, indole), 7.49 (t, J = 7.6 Hz, 1H, indole H-60), 7.87
(d, J = 5.1 Hz, 1H, NH), 8.95 (d, J = 7.9 Hz, 1H, indole H-40); 13C
NMR: d 13.98 (CH2CH3), 14.22 (CHCH3), 25.32 (NCH3), 26.02
(NCH3), 49.19 (NCH), 61.33 (OCH2), 79.84 (C-9a), 81.95 (C-3a),
109.63 (indole C-70), 119.64, 122.73, 124.24, 126.30, 127.36,
127.67, 127.99, 128.27, 131.84, 133.97, 134.72, 142.37
(indole C-70a), 148.77 (C═N), 159.13 (C═O), 159.43 (C═O),
166.81, 169.42 (indole C═O, ether C═O); HRMS-ESI:
m/z [M+ H] Anal. Calcd for C33H30N6O5S: 623.2071; found:
(Z)-Ethyl 2-(3-(1,3-dimethyl-2,7-dioxo-3a,9a-diphenyl-1,2,3,3a,
9,9a-hexahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-6(7H)-
ylidene)-2-oxo-1,2-dihydro-3H-indolyl-1-)acetate (3m). Thiscompound
was obtained as orange solid in 20% (method A) or 61%
1
(method B) yield, mp 262–265ꢁC; H NMR: d 1.23 (t, J=7.0Hz,
3H, CH3), 2.64 (s, 3H, N(3)CH3), 2.66 (s, 3H, N(1)CH3), 4.18
(q, J= 7.0 Hz, 2H, OCH2), 4.75 (s, 2H, NCH2), 6.77 (d, J=7.1Hz,
2H, phenyl), 6.84 (d, J= 7.4 Hz, 2H, phenyl), 7.05–7.21 (m, 8H,
phenyl, indole), 7.47 (t, J= 7.4 Hz, 1H, indole H-60), 7.79 (s, 1H,
NH), 8.91 (d, J= 7.9 Hz, 1H, indole H-40); 13C NMR: d 13.98
(CH3), 25.32 (NCH3), 26.00 (NCH3), 41.38 (NCH2), 61.32
(OCH2), 79.81 (C-9a), 81.90 (C-3a), 109.51 (indole C-70), 119.40,
122.83, 124.19, 126.28, 127.34, 127.53, 127.65, 127.89, 127.98,
128.24, 131.06, 131.83, 133.96, 134.71, 143.11 (indole C-70a),
148.71 (C═N), 159.11 (C═O), 159.41 (C═O), 167.28, 167.56
(indole C═O, ether C═O); HRMS-ESI: m/z [M + H] Anal. Calcd
for C32H28N6O5S: 609.1915; found: 609.1919.
623.2066.
(Z)-7-(1-Allyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-
dimethyl-3a,9a-diphenyl-1,3a,4,9a-tetrahydroimidazo[4,5-e]
thiazolo[2,3-c]-1,2,4-triazin-2,8(3H,7H)-dione (4k). To a solution of
thiazolotriazine 1 (0.20 g, 0.5 mmol) and isatin 2k (0.09 g,
0.5 mmol) in 15 mL of refluxing MeOH, 0.05 mL of 40%
aqueous KOH was added. The reaction mixture was stirred
under reflux for 30 min. Then 5 mL H2O were added and the
reaction mixture left to cool in a refrigerator overnight. The
separated solid product was filtered off and dried.
(Z)-2-(3-(1,3-Dimethyl-2,7-dioxo-3a,9a-diphenyl-1,2,3,3a,9,
9a-hexahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-6
(7H)-ylidene)-2-oxo-1,2-dihydro-3H-indolyl-1-)acetamide
This compound was obtained as scarlet powder in 55% yield,
mp 181–183.5ꢁC; 1H NMR: d 2.62 (s, 3H, N(3)CH3), 2.95
(s, 3H, N(1)CH3), 4.46 (d, J = 4.4 Hz, 2H, NCH2), 5.14 (m,
2H, =CH2), 5.81–5.95 (m, 1H, CH), 6.71 (br.s, 2H, phenyl),
6.96–7.27 (m, 10H, phenyl, indole), 7.34 (t, J = 7.6 Hz, 1H, indole
H-60), 8.42 (s, 1H, NH), 8.52 (d, J = 7.8 Hz, 1H, indole H-40); 13C
NMR: d 25.56 (N(3)CH3), 30.93 (N(1)CH3), 41.78 (NCH2),
81.46 (C-3a), 86.68 (C-9a), 109.40 (indole C-70), 116.91
(allyl═CH2), 119.59, 121.89, 122.21, 127.13, 127.18, 127.98,
128.46, 128.91, 130.68, 131.64, 131.66, 132.77, 133.75, 138.48
(C═N), 142.46 (indole C-70a), 158.13 (C(2)═O), 163.19
(C(8)═O), 166.94 (indole C═O); HRMS-ESI: m/z [M + H]
Anal. Calcd for C31H26N6O3S: 563.1860; found: 563.1861.
(3n).
This compound was obtained as orange solid in 10%
1
(method A) or 56% (method B) yield, mp 232–235ꢁC; H NMR:
2.65 (s, 3H, N(3)CH3), 2.66 (s, 3H, N(1)CH3), 4.46 (s, 2H,
NCH2), 6.77 (d, J = 6.9 Hz, 2H, phenyl), 6.84 (d, J = 7.1 Hz, 2H,
phenyl), 7.03–7.18 (m, 8H, phenyl, indole), 7.34 (s, 1H, NH2),
7.47 (t, J = 7.2 Hz, 1H, indole H-60), 7.75 (s, 1H, NH2), 7.86
(s, 1H, NH), 8.90 (d, J = 7.6 Hz, 1H, indole H-40); 13C NMR: d
25.30 (NCH3), 26.00 (NCH3), 42.45 (NCH2), 79.84 (C-9a), 81.86
(C-3a), 109.42 (indole C-70), 119.51, 122.53, 125.02, 126.27,
127.35, 127.66, 127.90, 127.99, 128.25, 130.03, 131.79, 133.96,
134.73, 143.85 (indole C-70a), 148.92 (C═N), 159.12 (C═O),
159.56 (C═O), 167.32, 167.90 (indole C═O, amide C═O);
HRMS-ESI: m/z [M + Na] Anal. Calcd for C30H25N7O4S:
602.1581; found: 602.1582.
REFERENCES AND NOTES
(Z)-Methyl 2-(3-(1,3-dimethyl-2,7-dioxo-3a,9a-diphenyl-1,2,3,3a,
9,9a-hexahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazin-6(7H)-
ylidene)-2-oxo-1,2-dihydro-3H-indolyl-1-)propanoate (3o). This
compound was obtained as orange powder in 17% (method A) or
63% (method B) yield, mp 285–288ꢁC; 1H NMR: d 1.60
(d, J= 7.0 Hz, 3H, CH3), 2.63 (s, 3H, N(3)CH3), 2.64 (s, 3H, N(1)
CH3), 3.68 (s, 3H, OCH3), 5.34 (q, J= 7.0 Hz, 1H, NCH), 6.76 (d,
J= 7.2 Hz, 2H, phenyl), 6.83 (d, J= 7.3 Hz, 2H, phenyl), 7.05–7.21
(m, 8H, phenyl, indole), 7.48 (t, J= 7.6 Hz, 1H, indole H-60), 7.84
(s, 1H, NH), 8.94 (d, J= 7.9 Hz, 1H, indole H-40); 13C NMR:
d 14.23 (CH3), 25.29 (NCH3), 26.00 (NCH3), 49.05 (NCH), 52.57
(OCH3), 79.83 (C-9a), 81.96 (C-3a), 109.54 (indole C-70), 119.63,
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