Target-oriented synthesis of functionalized pyrazolo-fused medium-sized N,S-heterocycles via Friedel–Crafts ring closure approach

Article abstract of DOI:10.1007/s10593-020-02822-1

[Figure not available: see fulltext.] Efficient and concise synthetic protocol to benzo- and pyrazolo-fused medium-sized N,S-heterocycles (e.g,. thiazocinones, thiazoninones, thiazecinones, thiecinones, and thioninones) is developed. The process involves

Full text of DOI:10.1007/s10593-020-02822-1

DOI 10.1007/s10593-020-02822-1
Chemistry of Heterocyclic Compounds 2020, 56(10), 1353–1362
Target-oriented synthesis of functionalized
pyrazolo-fused medium-sized N,S-heterocycles
via Friedel–Crafts ring closure approach
Hassan A. K. Abd El-Aal1*
1 Chemistry Department, Faculty of Science, Assiut University,
Assiut 71516, Egypt; e-mail: hassankotb33@yahoo.com; hassankotb@aun.edu.eg
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(10), 1353–1362
Submitted August 16, 2019
Accepted after revision January 23, 2020
R
O
( )n
( )y
O
CHO
Cl
Me
Friedel–Crafts
cycliacylation
HN
Me
N
Me
N
or
N
N
Ph
4–5 steps
( )n
N
N
S
S
Ph
Ph
y = 0, 1
n = 1, 2
R = H, Me
n = 0, 1
Efficient and concise synthetic protocol to benzo- and pyrazolo-fused medium-sized N,S-heterocycles (e.g,. thiazocinones, thia-
zoninones, thiazecinones, thiecinones, and thioninones) is developed. The process involves the AlCl3/MeNO2, TfOH or polyphosphoric
acid mediated cyclization of pyrazole-based carboxylic acids or esters into tricyclic ketones under mild conditions. The designed protocol
offers easy access to biologically and pharmaceutically promising pyrazoles in good yields. The structure elucidation of all new
compounds without stereochemical assignments has been carried out by spectral and elemental analysis.
Keywords: polycycles, pyrazoles, thiazocinones, thiecinones, Friedel–Crafts cycliacylation.
Condensed polycycles containing medium-ring N,S-hetero-
cycles are common structural motifs in many naturally
occurring alkaloids1 displaying wide range of pharma-
cological activities (Fig.1).2 The alliance of great structural
diversity and versatile pharmaceutical applicability of these
heterocycles have maintained the interest of both organic
and medicinal researchers toward the discovery of novel
bioactive architectures.3 Interestingly, numerous strategies
have been successfully applied to construct fused six- and
seven-membered heterocycles, including olefin meta-
thesis,4 Cope rearrangement,5 Mizoroki–Heck reaction,6
Diels–Alder reaction,7 ring expansion,8 Friedel–Crafts
reaction,9 cycloadditions,10 transition metal catalized cyclo-
addition,11 Heck-type coupling,12 sigmatropic cyclization,13
Baylis–Hillman reaction,14 domino15 and cascade16
strategies.
MeO
O
MeO
OH
Me
MeO
Me
N
N
N
Me
NMe
O
H
HO
H
MeO
N
H
Me
HO
OMe
Ethylketazocine
Galanthamine
Velbanamine
Protostephanine
MeN
Me
O
S
N
OMe
SH
O
H
N
N
Me
N
Me
N
Ph
N
O
Cl
O
O
H
S
O
S
Me
Diltiazem
Clotiapine
Omapatrilat
Figure 1. Examples of biologically active medium-sized N,S-heterocycles.
0009-3122/20/56(10)-1353©2020 Springer Science+Business Media, LLC
1353

Chemistry of Heterocyclic Compounds 2020, 56(10), 1353–1362
Figure 2. Some of polyheterocycles synthesized in the main step by Friedel–Crafts processes.
An examination of the literary precedents for the synthesis
of medium-sized N,S-heterocycles revealed that several
examples of benzo-annulated 1,3-, 1,4-, 1,5-thiazepine regio-
isomers have been explored.17 Interestingly, that synthesis of
1,2- and 1,3-thiazocines has been described only in few works.18
However, no information was found on the synthesis of
nine-membered and larger rings, except for the few
examples from some natural products families, e.g.,
erythrina, aspidosperma, and iboga alkaloids.19 The lack of
efficient protocols for the synthesis of eight-membered and
larger strained rings were attributed to the transannular
interactions20 (nonbonded repulsions) especially severe in
seven-membered and larger rings. Currently, several
approaches to the synthesis of the medium-sized hetero-
cycles21 have been utilized to overcome these barriers.
Among the most worthwhile strategies for accessing 1,4-
and 1,5-thiazocines described in the literature are ring-
closing metathesis of olefinic sulfones and sulfoxides using
Grubbs catalyst in CH2Cl2,22 Pd-catalyzed carbonylation/
cyclization of 2-(2-iodobenzylsulfanyl)-5-alkylbenzenamines,23
cyclization of aryl thioesters using LiHMDS in THF,24
cyclization of bromosulfanyl arenes in the presence of
LDA,25 ring expansion of the thiazolium salts,26 photo-
induced cyclization of phthalimidoalkylsulfanyl-based
carboxylic acids or esters,27 SnCl2-mediated cyclizations of
thiopyran hemiacetals,28 cyclization of iminoethers using
Amberlyst ion exchange resin,29 intramolecular Ugi
reaction of bifunctional oxoacids,30 cyclization of
thiophenol-based carboxylic acid using PCl5,31 cyclization
of 1-amino-8-bromonaphthalene thioethers using p-TsCl in
pyridine,32 and cyclization of 3-(benzhydrylsulfanyl)propanoic
acids using EDC in the presence of Hünig's base.24
Nevertheless, a few methods have been reported for the
synthesis of thiazonines or larger ring systems including
ring expansion of ω-bromoalkyl benzothiazolium salts,33
2,3-sigmatropic rearrangements of chloramine-T based
S-imides,34 and ring expansion of S-lactams using NaIO4.35
In this context, it is worth highlighting the great
importance of Friedel–Crafts reactions in the area of
medium-ring synthesis.36 Precedents in the literature have
shown that this type of processes is considered as
macrocyclization methodology37 and often adopted for the
construction of several homo- and heterocyclic skeletons,
e.g., thiazocines, pyrrolothienothiazocines, and benzo-
diazocines (Fig. 2).38
As an extension of our research program focused on
synthesizing drug-like heterocycles39 using Friedel–Crafts
cyclization,40 herein, we wish to report our attempts toward
the construction of pyrazole polycycles incorporating
pyrazole and medium-sized N-heterocycles in the new
molecular design, in particular, benzo- and pyrazolo-fused
8-, 9-, and 10-membered N,S-heterocycles utilizing
Brønsted and Lewis acids mediated Friedel–Crafts cycliza-
tions of presynthesized heterocyclic acids or esters.
The reaction sequences employed for the synthesis of
pyrazole-based ester 7a–d and acid 9a–d precursors
starting from pyrazole-4-carbaldehyde 1,41a are illustrated
in Scheme 1. Initially, the proposed synthetic pathway
involved the reaction of pyrazole-4-carbaldehyde 1 with
thiophenol or benzylmercaptan 2a,b41b in DMF to produce
substituted aldehydes 3a,b. The initial route (route a)
toward precursors 7a–d was started from aldehydes 3a,b.
This synthesis involved oxidation of aldehydes 3a,b using
KMnO4 to afford carboxylic acids 4a,b. Acids 4a,b
underwent the Schmidt42 reaction by treatment with NaN3/
H2SO4 to give aminopyrazoles 5a,b in good yields.
Alkylation of amines 5a,b with ethyl α- or β-bromo-
alkanoate 6a,b using K2CO3/DMF subsequently yields
ester precursors 7a–d.
The second route (route b) encompassed the formation
of heterocyclic acids 9a–d via the condensation of substrates
3a,b with AcONa or EtCO2Na and their corresponding acid
anhydrides followed by reduction of the resulting acrylic
acids 8a–d with sodium amalgam (Na/Hg, 2.5%), which
resulted in acid precursors 9a–d in good yields. With
starting compounds in hand, our further studies were
devoted to the development of facile and readily scalable
procedures to pyrazolo- and benzo-fused medium-sized 8–
1354

Chemistry of Heterocyclic Compounds 2020, 56(10), 1353–1362
Scheme 1
Scheme 2
10-membered N,S-heterocyclic systems proceeding via
Friedel–Crafts cyclization of precursors 7, 9 a–d.
Gratifyingly, with initial extensive investigations of mild
catalysts, solvents, and temperatures, the ring closures of
substrate 7a were demonstrated to be possible. At this
stage, a few attempts toward the formation of medium-
sized compound 10a were tried on substrate 7a using low
stoichiometric loadings of mild AlCl3/MeNO2, PPA, or
TfOH catalysts for 30 min at a certain temperature, which
afforded product 10a in poor yields. So we started
adjusting the reaction conditions by increasing the reaction
time at elevated temperatures with more than stoichio-
metric loadings of acid promoters. Out of several modi-
fications tried, the conditions outlined in Table 1 seemed
satisfactory to achieve the desired products 10, 11 a–d in
70–90% yields. With suitable conditions for this reaction,
Friedel–Crafts cycliacylation of functionalized precursors
containing more reactive arenes was feasible. The crude
products were purified several times by flash column
chromatography and crystallization.
These results demanded an explanation of the significant
role of catalysts in Friedel–Crafts cycliacylations in
heterocyclic system. First of all and after a literature
search, we found that the catalytic inhibitions43 of Lewis or
Brønsted acids are considered a major problem encountered
with inter- and intramolecular Friedel–Crafts processes in
heteroaromatics synthesis. This suggested that the rate of
the ring closure process is strongly dependent on the
catalyst strength. Conceivably, the ease of the cyclization
process depends mainly on the binding activity of acidic
catalysts on heteroatoms present in the substrate. Since the
stronger catalyst is the more it is complexed with hetero-
atoms and, hence, leads to the deactivation of a nucleo-
philic substrate and consequent retard the cyclization
process fully. Conversely, the mild catalyst is the less
coordinated with substrate heteroatoms.
Regarding the role of catalyst inhibition on slowing or
inhibiting ring closure of electron-rich arenes, we presume
that the weakly acidic catalysts are unable to coordinate
effectively with the heteroatoms. The result highlights the
utility of cyclization procedures which lies in the mildness
of selected catalysts, operating conditions, and functional
group compatibility in order to bring ring closure to
completion. The most important finding of cyclization
studies was the proposed mechanism44 for Friedel–Crafts
cycliacylations in heteroarenes. Mechanistically, we
proposed that acylation process would take place via an
initial treatment with acidic catalysts. This could result in
an acyl carbocation,45 either free or as an ion pair, by loss
of H2O or EtOH molecules. The acyl carbocation would
undergo cycliacylation into tricyclic scaffolds.
1355

Chemistry of Heterocyclic Compounds 2020, 56(10), 1353–1362
Table 1. Cyclization conditions of esters 7a–d and acids 9a–d
and yields of products 10, 11 a–d
11d indicates the absence of the diagnostic carboxylic acid
1
signal shown at 10.09 ppm in the H NMR spectrum of
acid 9d. Further, the characteristic changes in the 13C NMR
spectra proved that the cyclization process had occurred.
For example, the disappearance of the CO2H signal at
181.2 ppm in the 13C NMR spectrum of compound 9d and
the appearance of the new carbonyl group signal at
199.9 ppm in the 13C NMR spectrum of compound 11d.
Protons of the methylene groups in compounds 10, 11 a–d
are unequivalent and are represented as unresolved signals.
Time,
h
Yield,
Substrate
Method
Product
%
I*
II**
III***
I
15
6
81
78
73
84
80
75
78
72
70
79
81
75
83
74
75
79
82
80
81
77
75
85
80
73
4
1
12
5
Thus, the direct inspection of the H NMR spectrum of
ketones 11b,d displayed well-resolved two distinct
shielded and upfielded signals assigned to diastereotopic
protons of CH2 group.
II
III
I
4
In conclusion, we have designed an unprecedented and
concise catalytic protocol for the synthesis of tricyclic
benzo- and pyrazolo-fused medium-sized N,S-heterocyclic
ring systems incorporating 8-, 9-, and 10-membered rings
from simple starting materials via Friedel–Crafts cycli-
acylations of acyclic acids or esters precursors. Encou-
raging results confirmed our assumption that it should be
possible to synthesize polycyclic pyrazoles of promising
medicinal interest from the corresponding acyclic pre-
cursors using mild acidic catalysts that would be beneficial
to the synthetic community.
20
10
8
II
III
I
17
10
8
II
III
I
Experimental
17
8
IR spectra were obtained on a PerkinElmer 1600 FT-IR
spectrophotometer in KBr pellets. 1H and 13C NMR spectra
were recorded on a JEOL LA-400 FT-NMR (400 and
100 MHz, respectively) in CDCl3 with TMS as internal
standard. Elemental analyses were carried out by a vario
EL III 2400 CHNOS elemental analyzer. Melting points
were determined on a digital Gallenkamp capillary melting
point apparatus and are uncorrected. The progress of the
reactions was monitored by TLC on Silufol UV-254 silica
gel plates, visualized with UV light (at 254 and/or 360 nm).
Flash column chromatography was performed on Merck
silica gel (230–400 mesh).
All chemicals used were of reagent grade and solvents
were freshly distilled and dried by standard procedures
before use. 5-Chloro-3-methyl-1-phenyl-1H-pyrazole-
4-carbaldehyde (1) was prepared according to the literature
procedure.41
Synthesis of substituted pyrazole carbaldehydes 3a,b
(General method). A mixture of aldehyde 1 (20 mmol),
substituted thiophenol 2a or 2b (22 mmol), and K2CO3
(70 mmol) in DMF (20 ml) was heated with continuous
stirring for 5–6 h at 90–100°C, and the progress of the
reaction was monitored by TLC. After completion of the
reaction, the mixture was cooled and concentrated under
reduced pressure. The residue was poured into ice H2O
(100 ml), and the resulting precipitate was filtered off,
washed with H2O, dried, and recrystallized.
II
III
I
5
Me
18
10
7
Me
N
O
II
N
S
Ph
11b
III
I
O
20
8
Me
N
II
N
S
Ph
11c
III
I
6
16
9
II
III
6
* Method I: esters 7a–d or acids 9a–d (2 mmol) in CH2Cl2 (10 ml), AlCl3
(10 mmol), MeNO2 (100 mmol), room temperature.
** Method II: esters 7a–d or acids 9a–d (3 mmol), TfOH (1 ml, 12 mmol),
1,2-DCE (20 ml), reflux.
*** Method III: esters 7a–d or acids 9a–d (3 mmol), PPA (15 g), 160–180°C.
The formation of cyclic products 10, 11 a–d was proven
1
on the basis of H NMR, 13C NMR, and IR spectra. For
3-Methyl-1-phenyl-5-(phenylsulfanyl)-1H-pyrazole-
4-carbaldehyde (3a). Yield 4.53 g (77%), yellow crystals,
mp 68–70°C. IR spectrum, ν, cm–1: 3140, 3055, 2900,
example, a comparison of the spectroscopic data of acid 9d
and ketone 11d has clearly shown the disappearance of the
characteristic CO2H stretch found at 2630 cm–1 in the IR
1
2740, 1690, 1600, 1585, 1440, 1377, 1170, 790. H NMR
1
spectrum of acid 9d, and the H NMR spectrum of ketone
spectrum, δ, ppm: 2.35 (3H, s, CH3); 7.15–7.22 (3H, m,
1356

Chemistry of Heterocyclic Compounds 2020, 56(10), 1353–1362
H Ar); 7.24–7.27 (3H, m, H Ar); 7.32–7.36 (2H, m, H Ar);
1H NMR spectrum, δ, ppm: 2.39 (3H, s, CH3); 4.35 (2H, s,
CH2); 7.15–7.32 (6H, m, H Ar); 7.43–7.47 (2H, m, H Ar);
7.78–7.80 (2H, m, H Ar); 10.42 (1H, s, COOH). 13C NMR
spectrum, δ, ppm: 13.1 (CH3); 35.7 (CH2); 121.8; 124.7;
128.7; 128.9; 129.1; 129.2; 137.1; 139.3; 142.0 (C-3);
145.2 (C-5); 168.8 (C=O). Found, %: C 66.50; H 5.13;
N 8.80; S 9.84. C18H16N2O2S. Calculated, %: C 66.66;
H 4.93; N 8.64; S 9.87.
7.77–7.80 (2H, m, H Ar); 10.11 (1H, s, CHO). 13C NMR
spectrum, δ, ppm: 13.2 (CH3); 121.8; 124.7; 125.2; 129.2
(2C); 131.5; 131.7; 139.4; 142.1; 145.2; 189.2 (C=O).
Found, %: C 69.35; H 4.90; N 9.50; S 10.73. C17H14N2OS.
Calculated, %: C 69.38; H 4.76; N 9.52; S 10.88.
5-(Benzylsulfanyl)-3-methyl-1-phenyl-1H-pyrazole-
4-carbaldehyde (3b). Yield 5.42 g (88%), pale-yellow
crystals, mp 49–52°C (mp 52–54°C41b). IR spectrum, ν, cm–1:
3136, 3030, 2930, 2740, 1685, 1600, 1580, 1445, 1360, 1180,
755. 1H NMR spectrum, δ, ppm: 2.35 (3H, s, CH3); 4.43 (2H,
s, CH2); 7.15–7.22 (1H, m, H Ar); 7.24–7.26 (1H, m, H Ar);
7.28–7.35 (4H, m, H Ar); 7.40–7.43 (2H, m, H Ar); 7.73–7.75
(2H, m, H Ar); 10.10 (1H, s, CHO). 13C NMR spectrum,
δ, ppm: 12.5 (CH3); 28.0 (CH2); 118.5; 124.7; 129.2;
129.9; 131.5; 134.1; 137.5; 140.5; 150.2; 185.7 (C=O).
Found, %: C 70.33; H 5.15; N 8.91; S 10.25. C18H16N2OS.
Calculated, %: C 70.12; H 5.19; N 9.09; S 10.38.
Synthesis of pyrazole amines 5a,b (General method).
Ice-cold solution of KMnO4 (3.2 g, 20 mmol) in H2O
(7 ml) was added dropwise to a solution of aldehyde 3a,b
(5.4 g, 18 mmol) in Me2CO (30 ml) over 20 min with
efficient stirring. After complete addition, the mixture was
allowed to stir for 1 h at room temperature and then it was
heated on a steam bath at 70–80°C for 3 h. A solution of
10% KOH (30 ml) was slowly added to this mixture with
stirring until the solution turned alkaline, afterward, the
reaction mixture was filtered. Acidification of the resulting
filtrate to pH 3.0 using 30% HCl solution (50 ml) resulted
in a solid, which was filtered off, washed with H2O, and
dried yielding the crude acids 4a,b.
3-Methyl-1-phenyl-5-(phenylsulfanyl)-1H-pyrazol-
4-amine (5a). Yield 2.02 g (77%), white plates, mp 110–
112°C. IR spectrum, ν, cm–1: 3395, 3350, 2955, 1600,
1
1580, 1440, 1380, 1268, 779. H NMR spectrum, δ, ppm:
2.14 (3H, s, CH3); 7.13–7.16 (4H, m, H Ar); 7.22–7.26
(2H, m, H Ar); 7.41–7.45 (2H, m, H Ar); 7.63–7.65 (2H,
m, H Ar), 10.21 (2H, s, NH2). 13C NMR spectrum, δ, ppm:
11.4 (CH3); 121.8; 124.7; 125.2; 129.2; 131.5; 131.7;
137.5; 139.4; 152.0 (C-3); 155.7 (C-5). Found, %: C 68.22;
H 5.50; N 15.02; S 11.21. C16H15N3S. Calculated, %:
C 68.32; H 5.33; N 14.94; S 11.38.
5-(Benzylsulfanyl)-3-methyl-1-phenyl-1H-pyrazol-
4-amine (5b). Yield 2.18 g (74%), white plates, mp 142–
145°C. IR spectrum, ν, cm–1: 3453, 3160, 2939, 1690,
1
1610, 1580, 1445, 1385, 1170, 769. H NMR spectrum,
δ, ppm: 2.16 (3H, s, CH3); 4.31 (2H, s, CH2); 7.13–7.15
(1H, m, H Ar); 7.17–7.19 (1H, m, H Ar); 7.22–7.32 (4H,
m, H Ar); 7.40–7.44 (2H, m, H Ar); 7.62–7.64 (2H, m,
H Ar); 9.90 (2H, s, NH2). 13C NMR spectrum, δ, ppm: 11.4
(CH3); 35.7 (CH2); 121.8; 124.7; 128.7; 128.9; 129.1;
137.1; 137.4; 139.3; 152.0 (C-3); 155.6 (C-5). Found, %:
C 69.12; H 5.64; N 14.10; S 10.95. C17H17N3S. Calculated,
%: C 69.15; H 5.76; N 14.23; S 10.84.
NaN3 (0.8 g, 12 mmol) was added portionwise over
40 min to a stirred solution of acid 4a,b (10 mmol) in 30%
H2SO4 (15 ml) at 0–5°C. After complete addition, the
mixture was allowed to stir at ambient temperature for 1 h
and then it was heated with constant stirring at 60–70°C for
4 h. Again, the mixture was cooled to 0°C and then it
poured onto crushed ice (200 g), followed by the addition
of 50% NaOH solution (30 ml). The mixture was extracted
with EtOAc (3×50 ml), and the combined organic layer
was washed with brine, dried over MgSO4, concentrated
under reduced pressure, and purified with column
chromatography (basic alumina, CH2Cl2–hexane, 3:7) to
give the crude amines 5a,b.
Synthesis of esters 7a–d (General method). Haloester
6a,b (ethyl bromoacetate or ethyl bromopropionate)
(7 mmol) was added slowly to a hot (60–70°C) and stirred
mixture of amine 5a,b (5 mmol) and K2CO3 (15 mmol) in
DMF (15 ml) over 10 min. The mixture was heated at 90–
100°C for 4–6 h. When TLC analysis (EtOAc–hexane, 3:7)
showed the reaction to be complete, the mixture was cooled
to room temperature and poured into ice-cold H2O (300 m).
The resulting light solid was collected and washed
thoroughly with H2O and dried to afford the crude product.
This product was further purified by flash column
chromatography (basic alumina, EtOAc–hexane, 3:7).
Ethyl 2-[3-methyl-1-phenyl-5-(phenylsulfanyl)-1H-
pyrazol-4-ylamino]acetate (7a). Yield 1.56 g (85%),
white needles, mp 147–150°C (Me2CO). IR spectrum,
ν, cm–1: 3415, 3028, 2970, 1735, 1600, 1580, 1445, 1376,
3-Methyl-1-phenyl-5-(phenylsulfanyl)-1H-pyrazole-
4-carboxylic acid (4a). Yield 4.69 g (84%), white crystals,
mp 154–156°C. IR spectrum, ν, cm–1: 3410, 3050, 2966,
1
1
1690, 1600 1580, 1440, 1360, 1280, 1070, 775. H NMR
1290, 785. H NMR spectrum, δ, ppm (J, Hz): 1.15 (3H, t,
spectrum, δ, ppm: 2.39 (3H, s, CH3); 7.13–7.22 (3H, m,
H Ar); 7.23–7.27 (3H, m, H Ar); 7.38–7.42 (2H, m, H Ar);
7.78–7.80 (2H, m, H Ar); 9.94 (1H, s, COOH). 13C NMR
spectrum, δ, ppm: 13.2 (CH3); 121.8; 124.7; 125.2; 129.1;
129.2; 131.5; 131.7; 139.4; 142.1; 145.2; 168.8 (C=O).
Found, % C 65.87; H 4.66; N 8.84; S 10.46. C17H14N2O2S.
Calculated, %: C 65.80; H 4.51; N 9.03; S 10.32.
5-(Benzylsulfanyl)-3-methyl-1-phenyl-1H-pyrazole-
4-carboxylic acid (4b). Yield 5.02 g (86%), white crystals,
mp 185°C (decomp.). IR spectrum, ν, cm–1: 3440, 3070,
2946, 1688, 1605 1580, 1440, 1390, 1280, 1145, 784.
J = 7.1, CH2CH3); 2.13 (3H, s, CH3); 3.91 (2H, s, CH2CO);
4.14 (2H, q, J = 7.1, CH2CH3); 7.14–7.18 (4H, m, H Ar);
7.22–7.26 (2H, m, H Ar); 7.41–7.45 (2H, m, H Ar); 7.63–
7.65 (2H, m, H Ar); 9.88 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 11.4 (CH2CH3); 14.1 (CH3); 44.1 (CH2); 61.6
(CH2CH3); 121.8; 124.7; 125.2; 129.2; 131.5; 131.7; 137.5;
139.4; 152.0 (C-3); 155.7 (C-5); 171.1 (C=O). Found, %:
C 65.41; H 5.90; N 11.24; S 8.66. C20H21N3O2S. Calcu-
lated, %: C 65.39; H 5.72; N 11.44; S 8.71.
Ethyl 3-[3-methyl-1-phenyl-5-(phenylsulfanyl)-1H-
pyrazol-4-ylamino]propanoate (7b). Yield 1.56 g (82%),
1357

Chemistry of Heterocyclic Compounds 2020, 56(10), 1353–1362
white needles, mp 124–126°C (EtOH). IR spectrum, ν, cm–1:
1 N NaOH solution (20 ml) over 5 min. The reaction mixture
was stirred for 2 h at the same temperature, cooled, and
mercury was separated. The solution was filtered, and the
resulting clear filtrate was acidified with 30% HCl solution
(20 ml). After standing overnight in the refrigerator, the
resulting precipitate was collected, washed with H2O, and
then dried to afford the crude product 9.
(E)-3-[3-Methyl-1-phenyl-5-(phenylsulfanyl)-1H-
pyrazol-4-yl]acrylic acid (8a). Yield 3.73 g (74%), yellow
crystals, mp 155–158°C (Me2CO). IR spectrum, ν, cm–1:
3110, 3080, 2590, 1684, 1570, 1440, 1400, 1345, 1182,
782. 1H NMR spectrum, δ, ppm (J, Hz): 2.29 (3H, s, CH3);
6.50 (1H, d, J = 16.0, =CHCO); 7.11–7.30 (6H, m, H Ar);
7.45–7.49 (2H, m, H Ar); 7.76–7.80 (2H, m, H Ar); 7.78
(1H, d, J = 16.0, =CH); 10.09 (1H, s, COOH). 13C NMR
spectrum, δ, ppm: 13.1 (CH3); 119.9 (=CHCO); 121.8;
124.7; 125.1; 129.1; 129.2; 131.4; 131.6; 132.1; 139.3
(=CH); 142.0 (C-3); 145.2 (C-5); 167.6 (C=O). Found, %:
C 67.82; H 4.82; N 8.45; S 9.38. C19H16N2O2S. Calculated, %:
C 67.85; H 4.76; N 8.33; S 9.52.
3380, 3060, 2933, 1740, 1605, 1580, 1445, 1340, 1290,
1
778. H NMR spectrum, δ, ppm (J, Hz): 1.15 (3H, t,
J = 7.1, CH2CH3); 2.13 (3H, s, CH3); 2.52 (2H, t, J = 6.7,
CH2CO); 3.21 (2H, t, J = 6.7, CH2NH); 4.12 (2H, q,
J = 7.1, CH2CH3); 7.11–7.16 (4H, m, H Ar); 7.22–7.26
(2H, m, H Ar); 7.40–7.45 (2H, m, H Ar); 7.63–7.65 (2H,
m, H Ar); 10.02 (1H, s, NH). 13C NMR spectrum, δ, ppm:
11.4 (CH2CH3); 14.1 (CH3); 34.1 (CH2NH); 43.1 (CH2CO);
60.7 (CH2CH3); 121.8; 124.7; 125.2; 129.2; 131.5; 131.7;
137.5; 139.4; 152.0 (C-3); 155.7 (C-5); 172.0 (C=O).
Found, %: C 65.98; H 5.85; N 11.13; S 8.50. C21H23N3O2S.
Calculated, %: C 66.14; H 6.03; N 11.02; S 8.39.
Ethyl
2-[5-(benzylsulfanyl)-3-methyl-1-phenyl-1H-
pyrazol-4-ylamino]acetate (7c). Yield 1.48 g (78%), white
crystals, mp 162–165°C (Me2CO). IR spectrum, ν, cm–1:
3411, 3045, 2960, 1738, 1600, 1585, 1440, 1393, 1280,
789. 1H NMR spectrum, δ, ppm (J, Hz): 1.15 (3H, t, J = 7.1,
CH2CH3); 2.15 (3H, s, CH3); 3.85 (2H, s, CH2); 4.14 (2H,
q, J = 7.1, CH2CH3); 4.29 (2H, s, CH2CO); 7.18–7.28 (6H,
m, H Ar); 7.34–7.38 (2H, m, H Ar); 7.62–7.64 (2H, m,
H Ar); 10.20 (1H, s, NH). 13C NMR spectrum, δ, ppm: 11.4
(CH2CH3); 14.1 (CH3); 35.7 (CH2); 44.1 (CH2CO); 61.6
(CH2CH3); 121.8; 124.7; 128.8; 129.0; 129.1; 129.2; 137.1;
137.5; 139.4; 152.0 (C-3); 155.7 (C-5); 171.1 (C=O).
Found, %: C 66.10; H 6.15; N 11.09; S 8.17. C21H23N3O2S.
Calculated, %: C 66.14; H 6.03; N 11.02; S 8.39.
(E)-2-Methyl-3-[3-methyl-1-phenyl-5-(phenylsulfanyl)-
1H-pyrazol-4-yl]acrylic acid (8b). Yield 4.09 g (78%),
pale-yellow crystals, mp 139–142°C (Me2CO). IR spectrum,
ν, cm–1: 3115, 3053, 2610, 1682, 1600, 1480, 1400, 1340,
1
1273, 715. H NMR spectrum, δ, ppm: 2.07 (3H, s, CH3);
2.27 (3H, s, =CCH3); 7.11–7.29 (5H, m, H, Ar); 7.33–7.47
(3H, m, H Ar); 7.76–7.78 (2H, m, H Ar); 7.80 (1H, s,
=CH); 10.11 (1H, s, COOH). 13C NMR spectrum, δ, ppm:
13.1 (CH3); 15.8 (=CCH3); 121.8; 124.7; 125.1; 128.1
(=CCH3); 129.1; 129.2; 131.4; 131.6; 133.0; 139.3 (=CH);
142.0 (C-3); 145.2 (C-5); 172.8 (C=O). Found, %: C 68.47;
H 5.30; N 8.14; S 9.15. C20H18N2O2S. Calculated, %:
C 68.57; H 5.14; N 8.00; S 9.14.
Ethyl 3-[5-(benzylsulfanyl)-3-methyl-1-phenyl-1H-
pyrazol-4-ylamino]propanoate (7d). Yield 1.60 g (81%),
white crystals, mp 119–122°C (Me2CO). IR spectrum,
ν, cm–1: 3390, 3030, 2953, 1740, 1605, 1580, 1440, 1388,
1
1160, 775. H NMR spectrum, δ, ppm (J, Hz): 1.15 (3H, t,
J = 7.1, CH2CH3); 2.15 (3H, s, CH3); 2.52 (2H, t, J = 6.7,
CH2CO); 3.20 (2H, t, J = 6.7, CH2NH); 4.12 (2H, q, J = 7.1,
CH2CH3); 4.27 (2H, s, CH2); 7.15–7.28 (6H, m, H Ar);
7.34–7.38 (2H, m, H Ar); 7.62–7.64 (2H, m, H Ar); 9.81
(1H, s, NH). 13C NMR spectrum, δ, ppm: 11.4 (CH2CH3); 14.1
(CH3); 34.1 (CH2CO); 35.7 (CH2); 43.1 (CH2NH); 60.7
(CH2CH3); 121.8; 124.7 (C-4); 128.8; 128.9; 129.0; 129.2;
137.1; 137.5; 139.4; 152.0 (C-3); 155.7 (C-5); 172.0 (C=O).
Found, %: C 67.01; H 6.10; N 10.53; S 8.26. C22H25N3O2S.
Calculated, %: C 66.83; H 6.32; N 10.63; S 8.10.
(E)-3-[5-(Benzylsulfanyl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl]acrylic acid (8c). Yield 4.25 g (81%), cream-
colored crystals, mp 121–124°C (PhH). IR spectrum, ν, cm–1:
3150, 3033, 2585, 1688, 1570, 1440, 1370, 1282, 771.
1H NMR spectrum, δ, ppm (J, Hz): 2.26 (3H, s, CH3); 4.40
(2H, s, CH2); 6.48 (1H, d, J = 16.0, =CHCO); 7.16–7.20
(2H, m, H Ar); 7.27–7.28 (2H, m, H Ar); 7.37–7.39 (2H,
m, H Ar); 7.44–7.47 (2H, m, H Ar); 7.76–7.79 (2H, m,
H Ar) 7.78 (1H, d, J = 16.0, =CH); 10.16 (1H, s, COOH).
13C NMR spectrum, δ, ppm: 13.1 (CH3); 35.7 (CH2); 119.9
(=CHCO); 121.8; 124.7; 128.7; 128.9; 129.1; 129.2; 132.1;
137.1; 139.3 (=CH); 142.0 (C-3); 145.2 (C-5); 167.6
(C=O). Found, %: C 68.44; H 5.23; N 8.17; S 9.05.
C20H18N2O2S. Calculated, %: C 68.57; H 5.14; N 8.00;
S 9.14.
Synthesis of acrylic acids 9a–d (General method).
Compounds were obtained in two reaction steps starting from
aldehyde 1. Step 1. Et3N (20 mmol) was added to a stirred
suspension of aldehyde 1a,b (3.5 g, 15 mmol), acid anhydride
(acetic or propionic anhydride) (18 mmol), and the sodium
salt of the corresponding acid (18 mmol). The mixture was
heated at 120–130°C for 4–5 h, cooled to room tempe-
rature, and then poured with stirring onto crushed ice (300 g).
The hydrolyzed mother liquor was basified with 30% Na2CO3
solution (40 ml) and extracted with EtOAc (3×30 ml). The
resulting aqueous solution was heated with decolorizing
carbon (2 g) for 10 min and then filtered. The clear filtrate
was poured while it still hot into the ice-cold 30% HCl
solution (100 ml). The precipitate of compound 8a–d was
collected, washed with H2O, and dried.
(E)-3-[5-(Benzylsulfanyl)-3-methyl-1-phenyl-1H-pyrazol-
4-yl]-2-methylacrylic acid (8d). Yield 4.15 g (76%), white
plates, mp 165–168°C (PhH). IR spectrum, ν, cm–1: 3205,
3030, 2965, 2670, 1685, 1585, 1470, 1440, 1394, 1270,
1
779. H NMR spectrum, δ, ppm: 2.10 (3H, s, CH3); 2.22
(3H, s, CH3); 4.41 (2H, s, CH2); 7.18–7.20 (2H, m, H Ar);
7.27–7.28 (2H, m, H Ar); 7.34–7.38 (2H, m, H Ar); 7.75–
7.78 (2H, m, H Ar); 7.78 (1H, s, =CH); 10.22 (1H, s,
COOH). 13C NMR spectrum, δ, ppm: 13.1 (CH3); 15.8
(=CCH3); 35.7 (CH2); 121.8; 124.7 (C-4); 128.1 (=CCH3);
128.7; 128.9; 129.1; 129.2; 133.0; 137.1; 139.3 (=CH);
Step 2. Na/Hg (25 g, 2.5%) was added portionwise to a
hot (40–50°C) stirred solution of acid 8a–d (10 mmol) in
1358

Chemistry of Heterocyclic Compounds 2020, 56(10), 1353–1362
142.0 (C-3); 145.2 (C-5); 172.8 (C=O). Found, %: C 69.31;
Ring closure of heterocyclic esters 7a–d and acids 9a–d
(General procedure). Method I. A solution of ester 7a–d or
acid 9a–d (2 mmol) in CH2Cl2 (10 ml) was added dropwise
to AlCl3 (10 mmol) in MeNO2 (100 mmol) over 10 min at
ambient temperature. The mixture was stirred for the time
given in Table 1. Afterward, the mixture was quenched
with ice-cold 10% HCl solution (20 ml) and extracted with
Et2O (3×20 ml). The combined organic layer was washed
twice with H2O and 10% Na2CO3 (20 ml). After drying the
organic layer over MgSO4 and filtration, the solution was
evaporated under reduced pressure to give the crude
products 10, 11 a–d.
Method II. TfOH (12 mmol) was added dropwise to a
cooled (0°C) solution of ester 7a–d or acid 9a–d (3 mmol)
in DCE (20 ml), and the mixture was stirred with reflux for
the time given in Table 1. Thereafter, the mixture was
quenched by aqueous 50% NaHCO3 solution (50 ml) at 0°C
and the product was extracted with EtOAc (3×30 ml). The
organic extracts were washed with H2O, dried over
anhydrous Na2SO4, and evaporated under reduced pressure
to give the crude products 10, 11 a–d.
H 5.52; N 7.55; S 8.83. C21H20N2O2S. Calculated, %:
C 69.23; H 5.49; N 7.69; S 8.79.
2-Methyl-4-[3-methyl-1-phenyl-5-(phenylsulfanyl)-
pyrazol-4-yl]butanoic acid (9a). Yield 3.01 g (89%), pale-
yellow solid, mp 142–145°C (Me2CO). IR spectrum, ν, cm–1:
3030, 2928, 2675, 1720, 1600, 1590, 1500, 1440, 1282,
1170, 768. 1H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, s,
CH3); 2.57 (2H, t, J = 7.4, CH2); 3.03 (2H, t, J = 7.4,
CH2CO); 7.14–7.24 (4H, m, H Ar); 7.26–7.32 (4H, m,
H Ar); 7.71 (2H, m, H Ar); 10.52 (1H, s, COOH). 13C NMR
spectrum, δ, ppm: 13.2 (CH3); 30.1 (CH2CO); 34.3 (CH2);
121.8; 124.7; 125.2; 129.1; 129.2; 131.5; 131.7; 139.4;
142.1 (C-3); 145.2 (C-5); 177.7 (C=O). Found, %: C 67.48;
H 5.35; N 8.15; S 9.55. C19H18N2O2S. Calculated, %:
C 67.45; H 5.32; N 8.28; S 9.46.
2-Methyl-3-[3-methyl-1-phenyl-5-(phenylsulfanyl)-
pyrazol-4-yl]propanoic acid (9b). Yield 3.16 g (90%),
pale-yellow solid, mp 111–114°C (Me2CO). IR spectrum,
ν, cm–1: 3050, 2930, 2664, 1715, 1600, 1590, 1440, 1400,
1
1266, 1170, 794. H NMR spectrum, δ, ppm (J, Hz): 1.15
(3H, d, J = 6.8, CHCH3); 2.30 (3H, s, CH3); 2.73 (1H, tq,
J = 7.5, J = 6.8, CHCO); 2.90 (2H, d, J = 7.5, CH2); 7.13–
7.20 (4H, m, H Ar); 7.22–7.32 (4H, m, H Ar); 7.70–7.72
(2H, m, H Ar); 10.48 (1H, s, COOH). 13C NMR spectrum,
δ, ppm: 13.2 (CH3); 16.8 (CCH3); 32.1 (CHCO); 39.1
(CH2); 121.8; 124.7 (C-4); 125.2; 129.1; 129.2; 131.5;
131.7; 139.4; 142.1 (C-3); 145.2 (C-5); 181.2 (C=O).
Found, %: C 67.97; H 5.59; N 8.09; S 9.16. C20H20N2O2S.
Calculated, %: C 68.18; H 5.68; N 7.95; S 9.09.
4-[(5-Benzylsulfanyl)-3-methyl-1-phenylpyrazol-4-yl]-
2-methylbutanoic acid (9c). Yield 3.06 g (87%), pale-
yellow plates, mp 137–140°C (PhH). IR spectrum, ν, cm–1:
3065, 2933, 2670, 1730, 1600, 1590, 1440, 1400, 1255,
1170, 780. 1H NMR spectrum, δ, ppm (J, Hz): 2.27 (3H, s,
CH3); 2.54 (2H, t, J = 7.4, CH2); 2.95 (2H, t, J = 7.4, CH2);
4.28 (2H, s, CH2); 7.12–7.20 (3H, m, H Ar); 7.27–7.28
(3H, m, H Ar); 7.37–7.41 (2H, m, H Ar); 7.70–7.72 (2H,
m, H Ar); 10.24 (1H, s, COOH). 13C NMR spectrum,
δ, ppm: 13.2 (CH3); 30.1 (CH2); 34.3 (CH2); 35.7 (CH2);
121.8; 124.7; 128.8; 128.9; 129.0; 129.2; 137.1; 139.4;
142.1 (C-3); 145.2 (C-5); 177.7 (C=O). Found, %: C 68.30;
H 5.53; N 8.13; S 9.02. C20H20N2O2S. Calculated, %:
C 68.18; H 5.68; N 7.95; S 9.09.
3-[(5-Benzylsulfanyl)-3-methyl-1-phenylpyrazol-4-yl]-
2-methylpropanoic acid (9d). Yield 3.22 g (88%), white
crystals, mp 139–142°C (Me2CO). IR spectrum, ν, cm–1:
3045, 2970, 2630, 1718, 1585, 1440, 1325, 1265, 1075,
760. 1H NMR spectrum, δ, ppm (J, Hz): 1.15 (3H, d, J = 6.8,
CHCH3); 2.28 (3H, s, CH3); 2.73 (1H, tq, J = 7.0, J = 6.8,
CHCO); 2.86 (2H, d, J = 7.0, CH2); 4.28 (2H, s, CH2); 7.13–
7.20 (3H, m, H Ar); 7.26–7.28 (3H, m, H Ar); 7.37–7.41
(2H, m, H Ar); 7.69–7.72 (2H, m, H Ar); 10.09 (1H, s,
COOH). 13C NMR spectrum, δ, ppm: 13.2 (CH3); 16.8
(CCH3); 32.1 (CH2CO); 35.7 (CH2); 39.1 (CH2); 121.8;
124.7; 128.8; 128.9; 129.1; 129.2; 137.1; 139.4; 142.1
(C-3); 145.2 (C-5); 181.2 (C=O). Found, %: C 68.80;
H 6.17; N 7.62; S 8.55. C21H21N2O2S. Calculated, %:
C 68.85; H 6.01; N 7.65; S 8.74.
Method III. A mixture of ester 7a–d or acid 9a–d
(3 mmol) and PPA (15 g) was heated on an oil bath at 160–
180°C for the time given in Table 1. Completion of the
reaction was monitored by TLC (EtOAc–hexane, 2:8).
Then the mixture was cooled to room temperature and
made alkaline by addition of 50% NaHCO3 solution (40 ml)
and then extracted with Et2O (3×30 ml). The combined
organics were washed with saturated brine solution, dried
over MgSO4, filtered, and concentrated under reduced
pressure to afford the desired products 10, 11 a–d.
In all procedures, the crude residue was purified by flash
chromatography (basic alumina, EtOAc–hexane, 1:4) to
afford the pure tricyclic products 10, 11 a–d.
6-Methyl-4-phenyl-2-thia-4,5,8-triazatricyclo[9.4.0.03,7]-
pentadeca-1(11),3(7),5,12,14-pentaen-10-one (10a). Yield
0.52 g (81%, method I), 0.75 g (78%, method II), 0.70 g
(73%, method III), pale-yellow crystals, mp 184°C (decomp.,
Me2CO). IR spectrum, ν, cm–1: 3412, 3077, 2930, 1700,
1600, 1590, 1440, 1370, 1289, 779. 1H NMR spectrum, δ, ppm
(J, Hz): 2.14 (3H, s, CH3); 4.65 (2H, s, 5-CH2); 7.12–7.16
(1H, m, H Ar); 7.41–7.47 (3H, m, H Ar); 7.63–7.67 (4H,
m, H Ar); 7.89–7.92 (1H, m, H Ar); 9.93 (1H, s, NH).
13C NMR spectrum, δ, ppm: 11.4 (CH3); 49.6 (C-5); 121.8;
124.7; 126.9; 127.5; 129.2; 129.4; 129.8; 131.5; 137.5;
138.3; 139.4; 152.0; 155.7; 191.7 (C=O). Found, %:
C 67.41; H 4.80; N 12.86; S 9.78. C18H15N3OS. Calculated, %:
C 67.28; H 4.67; N 13.08; S 9.96.
6-Methyl-4-phenyl-2-thia-4,5,8-triazatricyclo[10.4.0.03,7]-
hexadeca-1(12),3(7),5,13,15-pentaen-11-one (10b). Yield
0.56 g (84%, method I), 0.78 g (80%, method II), 0.74 g
(75%, method III), yellow crystals, mp 141–144°C
(Me2CO). IR spectrum, ν, cm–1: 3420, 3030, 2956, 1696,
1600, 1590, 1480, 1440, 1350, 1280, 788. 1H NMR
spectrum, δ, ppm (J, Hz): 2.13 (3H, s, CH3); 2.81 (2H, ddd,
J = 14.0, J = 8.8, J = 5.8, 6-CH2); 3.50 (2H, ddd, J = 9.2,
J = 8.8, J = 1.4, 5-CH2); 7.12–7.16 (1H, m, H Ar); 7.41–
7.45 (2H, m, H Ar); 7.46–7.51 (1H, m, H Ar); 7.54–7.59
(1H, m, H Ar); 7.62–7.65 (2H, m, H Ar); 7.70–7.72 (1H,
1359

Chemistry of Heterocyclic Compounds 2020, 56(10), 1353–1362
1
m, H Ar); 7.85–7.87 (1H, m, H Ar); 10.22 (1H, s, NH).
1385, 1289, 788. H NMR spectrum, δ, ppm (J, Hz): 1.14
(3H, d, J = 6.6, 5-CH3); 2.31 (3H, s, CH3); 3.06–3.08 (2H,
m, 4-CH2); 3.24–3.29 (1H, m, 5-CH); 7.15–7.20 (1H, m,
H Ar); 7.28–7.32 (2H, m, H Ar); 7.37–7.40 (1H, m, H Ar);
7.56–7.58 (1H, m, H Ar); 7.66–7.75 (3H, m, H Ar); 7.89–
7.91 (1H, m, H Ar). 13C NMR spectrum, δ, ppm: 13.2
(CH3); 15.7 (CH3); 32.1 (C-4); 44.2 (C-5); 121.8; 124.7;
126.9; 127.5; 129.2; 129.3; 129.4; 129.8; 131.5; 138.3;
139.4; 142.1; 145.2; 199.9 (C=O). Found, %: C 71.92;
H 5.40; N 8.32; S 9.37. C20H18N2OS. Calculated, %:
C 71.85; H 5.38; N 8.38; S 9.58.
13C NMR spectrum, δ, ppm: 11.4 (CH3); 38.9 (C-5); 43.1
(C-6); 121.8; 124.7; 126.9; 127.5; 129.2; 129.4; 129.8;
131.5; 137.5; 138.3; 139.4; 152.0; 155.7; 199.2 (C=O).
Found, %: C 68.20; H 5.19; N 12.50; S 9.33. C19H17N3OS.
Calculated, %: C 68.05; H 5.07; N 12.53; S 9.55.
7-Methyl-5-phenyl-3-thia-5,6,9-triazatricyclo[10.4.0.04,8]-
hexadeca-1(12),4(8),6,13,15-pentaen-11-one (10c). Yield
0.51 g (78%, method I), 0.72 g (72%, method II), 0.69 g
(70%, method III), yellow solid, mp 154–157°C (Me2CO).
IR spectrum, ν, cm–1: 3390, 3040, 2973, 1713, 1600, 1590,
1
1470, 1384, 1260, 785. H NMR spectrum, δ, ppm: 2.15
7-Methyl-5-phenyl-3-thia-5,6-diazatricyclo[10.4.0.04,8]-
hexadeca-1(12),4(8),6,13,15-pentaen-11-one (11c). Yield
0.51 g (81%, method I), 0.80 g (77%, method II), 0.75 g
(75%, method III), yellow needles, mp 161–163°C (EtOAc).
IR spectrum, ν, cm–1: 3025, 2940, 1690, 1600, 1580, 1445,
(3H, s, CH3); 4.55 (2H, s, 11-CH2); 4.67 (2H, s, 5-CH2);
7.17–7.26 (2H, m, H Ar); 7.34–7.39 (3H, m, H Ar); 7.49–
7.51 (1H, m, H Ar); 7.62–7.64 (2H, m, H Ar); 7.90–7.93
(1H, m, H Ar); 10.14 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 11.4 (CH3); 35.7 (C-11); 49.6 (C-5); 121.8; 124.7;
125.9; 128.4; 129.2; 130.5; 132.4; 133.0; 133.2; 137.5;
139.4; 152.0; 155.7; 195.0 (C=O). Found, %: C 68.09;
H 5.22; N 12.58; S 9.35. C19H17N3OS. Calculated, %:
C 68.05; H 5.07; N 12.53; S 9.55.
1
1370, 1240, 772. H NMR spectrum, δ, ppm (J, Hz): 2.27
(3H, s, CH3); 2.99–3.05 (4H, m, 4,5-CH2); 4.64 (2H, s,
11-CH2); 7.15–7.22 (2H, m, H Ar); 7.36–7.41 (3H, m,
H Ar); 7.46–7.50 (1H, m, H Ar); 7.69–7.71 (2H, m, H Ar);
7.80–7.82 (1H, m, H Ar). 13C NMR spectrum, δ, ppm: 13.2
(CH3); 30.1 (C-4); 35.7 (C-5); 38.8 (C-11); 121.8; 124.7;
125.9; 128.4; 129.2; 130.5; 132.4; 133.0; 133.2; 139.4;
142.1; 145.2; 206.8 (C=O). Found, %: C 71.99; H 5.51;
N 8.24; S 9.45. C20H18N2OS. Calculated, %: C 71.85; H 5.38;
N 8.38; S 9.58.
7-Methyl-5-phenyl-3-thia-5,6,9-triazatricyclo[11.4.0.04,8]-
heptadeca-1(13),4(8),6,14,16-pentaen-12-one (10d). Yield
0.54 g (79%, method I), 0.82 g (81%, method II), 0.77 g
(75%, method III), white crystals, mp 170–173°C (EtOH).
IR spectrum, ν, cm–1: 3410, 3050, 2920, 1714, 1600, 1585,
1470, 1385, 1280, 779. 1H NMR spectrum, δ, ppm (J, Hz):
2.15 (3H, s, CH3); 2.76 (2H, ddd, J = 15.4, J = 10.1,
J = 3.3, 6-CH2); 3.34 (2H, ddd, J = 11.5, J = 10.1, J = 2.0,
5-CH2); 4.09 (2H, s, 12-CH2); 7.19–7.26 (2H, m, H Ar);
7.34–7.38 (3H, m, H Ar); 7.46–7.51 (1H, m, H Ar); 7.62–
7.64 (2H, m, H Ar); 7.75–7.78 (1H, m, H Ar); 9.81 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 11.4 (CH3); 35.7 (C-12);
38.9 (C-5); 43.1 (C-6); 121.8; 124.7; 125.9; 128.4; 129.2;
130.5; 132.4; 133.0; 133.2; 137.5; 139.4; 152.0; 155.7;
199.2 (C=O). Found, %: C 68.59; H 5.28; N 12.17; S 9.02.
C20H19N3OS. Calculated, %: C 68.76; H 5.44; N 12.03;
S 9.16.
7,10-Dimethyl-5-phenyl-3-thia-5,6-diazatricyclo-
[10.4.0.04,8]hexadeca-1(12),4(8),6,13,15-pentaen-11-one
(11d). Yield 0.62 g (85%, method I), 0.82 g (80%, method II),
0.76 g (73%, method III), white crystals, mp 150–153°C
(Me2CO). IR spectrum, ν, cm–1: 3038, 2968, 1700, 1600,
1575, 1440, 1383, 1270, 1162, 779. 1H NMR spectrum, δ, ppm
(J, Hz): 1.17 (3H, d, J = 6.6, 5-CH3); 2.28 (3H, s, CH3);
3.01 (2H, d, J = 6.0, CH2); 3.50–3.70 (1H, m, 5-CH); 4.23
(1H, d, J = 16.6, 11-CH2); 4.44 (1H, d, J = 16.6, 11-CH2);
7.13–7.17 (1H, m, H Ar); 7.28–7.30 (1H, m, H Ar); 7.34–
7.41 (3H, m, H Ar); 7.46–7.50 (1H, m, H Ar); 7.69–7.71
(2H, m, H Ar); 7.74–7.76 (1H, m, H Ar). 13C NMR
spectrum, δ, ppm: 13.2 (CH3); 15.7 (CH3); 32.1 (C-4); 35.7
(C-5); 44.2 (C-11); 121.8; 124.7; 125.9; 128.4; 129.2; 130.5;
132.4; 133.0; 133.2; 139.4; 142.1; 145.2; 199.9 (C=O).
Found, %: C 72.40; H 5.91; N 7.93; S 9.32. C21H20N2OS.
Calculated, %: C 72.41; H 5.74; N 8.04; S 9.19.
6-Methyl-4-phenyl-2-thia-4,5-diazatricyclo[9.4.0.03,7]-
pentadeca-1(11),3(7),5,12,14-pentaen-10-one (11a). Yield
0.52 g (83%, method I), 0.71 g (74%, method II), 0.71 g
(75%, method III), yellow crystals, mp 190°C (decomp.,
PhH). IR spectrum, ν, cm–1: 3015, 2940, 1688, 1600, 1485,
1440, 1389, 1245, 770. 1H NMR spectrum, δ, ppm (J, Hz):
2.30 (3H, s, CH3); 2.90 (2H, ddd, J = 16.8, J = 6.3, J = 2.1,
4-CH2); 3.19 (2H, ddd, J = 10.2, J = 6.3, J = 2.1, 5-CH2);
7.17–7.19 (1H, m, H Ar); 7.28–7.32 (2H, m, H Ar); 7.37–
7.39 (1H, m, H Ar); 7.56–7.58 (1H, m, H Ar); 7.66–7.73
(3H, m, H Ar); 7.89–7.91 (1H, m, H Ar). 13C NMR
spectrum, δ, ppm: 13.2 (CH3); 30.1 (C-4); 38.8 (C-5);
121.8; 124.7; 126.9; 127.5; 129.2; 129.3; 129.4; 129.8;
131.5; 138.3; 139.4; 142.1; 145.2; 199.2 (C=O). Found, %:
C 71.29; H 5.17; N 8.65; S 10.08. C19H16N2OS. Calculated, %:
C 71.25; H 5.00; N 8.75; S 10.00.
Supplementary information file containing H and 13C
NMR spectra of all synthesized compounds is available at
the journal website at http://link.springer.com/journal/10593.
1
The author is grateful for all the facilities received while
performing and writing this work by the Chemistry
department, Faculty of science Assiut University, Assiut,
Egypt.
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