Synthesis and anti-inflammatory activity of 1,2-3-substituted 2a1,4,5-triazacyclopenta[cd]indene derivatives

Article abstract of DOI:10.1007/s00044-019-02386-6

The present study reports the synthesis of 1,2-3-substituted-2a1,4,5-triazacyclopenta[cd]indene derivatives. The synthetic methodology includes some of the prominent reaction steps as specified in sequence (i) Bromination of acetophenones (ii) Condensation of 2-bromo-1-(substituted phenyl) ethanone derivatives with 2-aminopyrimidine, and (iii) Coupling of imidazo[1,2-a]pyrimidine derivatives with 1,2-diaryl/diaklylethynes. The structures of the newly synthesized derivatives have been determined by ¹H NMR, ¹³C NMR, LC-MS, and IR spectral analysis. Furthermore, these derivatives were screened for their preliminary anti-inflammatory activities using Carrageenan induced paw edema test method. These promising screening results suggested a huge potential for the molecular diversity from present compounds that can be inflated to better lead candidates.

Full text of DOI:10.1007/s00044-019-02386-6

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02386-6
ORIGINAL RESEARCH
Synthesis and anti-inflammatory activity of 1,2-3-substituted
2
a1,4,5-triazacyclopenta[cd]indene derivatives
Sumalatha Sanivarapu1,2 Namratha Vaddiraju Lakshmi Velide4
3 ●
●
Received: 6 January 2019 / Accepted: 18 June 2019
©
Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
The present study reports the synthesis of 1,2-3-substituted-2a1,4,5-triazacyclopenta[cd]indene derivatives. The synthetic
methodology includes some of the prominent reaction steps as specified in sequence (i) Bromination of acetophenones (ii)
Condensation of 2-bromo-1-(substituted phenyl) ethanone derivatives with 2-aminopyrimidine, and (iii) Coupling of
imidazo[1,2-a]pyrimidine derivatives with 1,2-diaryl/diaklylethynes. The structures of the newly synthesized derivatives
1
13
have been determined by H NMR, C NMR, LC-MS, and IR spectral analysis. Furthermore, these derivatives were
screened for their preliminary anti-inflammatory activities using Carrageenan induced paw edema test method. These
promising screening results suggested a huge potential for the molecular diversity from present compounds that can be
inflated to better lead candidates.
●
●
●
●
●
Keywords Acyl bromides 2-Aminopyrimidine Anti-inflammatory Synthesis Imidazo[1 2-a] pyrimidines
Introduction
attention due to their biological and pharmacological activ-
ities (Sanjay et al. 2015, 2016). Imidazo [1,2-a]pyridines and
alkynes have been used as substrates for the preparation of
poly-cyclic heteroaromatic compounds in the presence of
Palladium catalyst and in the presence of oxidizing agents
(Xuesen Li et al. 2015). Imidazopyridines also exhibit
widest range of biological activities such as anti helminthic,
anti fungal (Michael and Aino 1972), anti tumor (William
et al. 1991), anti viral (Song et al. 2015), anti-bacterial
(Rival et al. 1992), anti protozoal, anti-pyretic, and anti
anxiety agents (Avik et al. 2015; Lucyna 2015). Closest to
the above fused heterocycle motifs are imidazopyrimidines
that are found in several natural, as well as synthetic bio-
logically active molecules (Fewell and Woolford 1999).
Imidazopyrimidine derivatives were proved to have several
properties like anti-bacterial (Rival et al. 1992), anti fungal
Over the past few years there is considerable interest in the
synthesis and pharmacological studies of heteroaromatic
organic compounds like imidazopyridines, imidazopyr-
imidines, etc since they possess promising biological
activity like anticancer activity (Kim et al. 2011; Yoshiyuki
et al. 2009). Synthesis and construction of fused poly-cyclic
heteroaromatic compounds via transition-metal-catalyzed
C–H bond functionalization has become an increasingly
important tool in recent years as this process provides a
simple, direct, and atom-economic access to π-conjugated
heteroaromatic molecules (Sanjay et al. 2016). These
polycyclic heteroaromatic compounds attracted considerable
(
Rival et al. 1991), analgesic, anti-inflammatory (Simon
*
Sumalatha Sanivarapu
sumalatha0529@gmail.com
et al. 2006), (Gaozhi et al. 2013), anti-pyretic, and anti-
convulsant activities (Ulloora et al. 2013).
1
2
3
4
Inspired by the above mentioned reaction sequence, we
report herein the synthesis and anti-inflammatory activity of
some new imidazo (1,2-a) pyrimidine derivatives utilizing
2-amino-pyrimidine and alkyl/aryl alkynes as starting
materials followed by further derivatizing to new class of
1,2,3-substituted-2a1,4,5-triazacyclopenta[cd]indene com-
pounds 25–36. To the best of our knowledge, these new
derivatives have not been reported in the literature so far.
Department of Chemistry, Jawaharlal Nehru Technological
University, Hyderabad, Telangana 500072, India
Green Evolution Laboratories, Wangapally Village,
Nalgonda, Telangana 508286, India
Department of Chemistry, Satavahana University,
Karimnagar, Telangana 505002, India
Department of Life Sciences, Kakatiya University,
Warangal, Telangana 506009, India

Medicinal Chemistry Research
Experimental section
poured into ice-water (30 mL) with vigorous stirring and the
organic layer i.e., 2-Me-tetrahydrofuran containing was
Materials and methods
separated, dried over anhydrous MgSO , filtered and eva-
4
porated under reduced pressure to obtain the corresponding
2-phenylimidazo[1,2-a]pyrimidine 14–19. Two of the
representative derivatives (15 and 17) were characterized by
H NMR, Mass and HPLC for purity and remaining all
isolated compounds were directly utilized in the next with-
All chemicals and reagents were obtained from Aldrich
(
Sigma–Aldrich, St. Louis, MO, USA), Lancaster (Alfa
1
Aesar, Johnson Matthey Company, Ward Hill, MA, USA)
and were used without further purification. Reactions were
monitored by TLC, performed on silica-gel glass plates
containing 60 F-254, and visualization on TLC was
out further purification.
1
13
achieved by UV light or iodine indicator. H and C NMR
spectra were recorded on Bruker, Bruker UXNMR/XWIN-
NMR (500 MHz, 400 MHz, 300 MHz) instrument. Chemi-
cal shifts (δ) are reported in ppm downfield from internal
TMS standard. ESI spectra were recorded on Micro mass,
Quattro LC using ESI+ software with capillary voltage
General procedure for the synthesis of 1,2-3-
substituted 2a1,4,5-triazacyclopenta[cd]indene
derivatives (25–36)
To a stirred solution of DMF (1 mL):PEG-1500 (1 g) in a
sealed tube was added sequentially 2-phenylimidazo[1,2-a]
3
.98 kV and ESI mode positive ion trap detector. Melting
pyridine 14–19 (100 mg, 0.2 mmol), Pd(OAc) (0.02 mmol),
2
points were determined with an electro thermal melting
point apparatus, and are uncorrected. The LCMS purity of
the final compounds were determined under the following
optimized condition using “Column: KINETEX-1.7 µ XB-
C18 100 A (2.1 × 50 mm); Mobile phase A: 0.05% FA in
Cu(OAc) (0.04 mmol), 1,2-diphenylethynes 20–24 (0.3 mmol)
2
and TBAB (0.2 mmol) (Sanjay et al. 2016). The reaction
mixture was heated to 90 °C for 12 h. After completion of
the reaction (monitored by TLC), the reaction mixture was
quenched with aqueous NH Cl and extracted with iso-
4
H O; Mobile phase B: 0.05% FA in ACN; T/%A: 0/97,
2
propylacetate (10 mL × 3). The combined organic layer was
0
.3/97, 3.2/2, 4.8/2, 5/97, 5.10/97; Flow rate: 0.6 mL/min,
washed with brine, dried over anhydrous MgSO , filtered and
4
Temp: 35 °C.
concentrated under vacuum and the crude product was
purified by chromatography on silica-gel to afford the desired
1
General procedure for synthesis of α-haloketones
1,2-3-substituted 2a ,4,5-triazacyclopenta[cd]indene deriva-
(7–12)
tives 25–34. The yields of the products varied between
61–82%.
To a solution of acetophenones 1–6 (16.65 mmol) in 2-Me-
tetrahydrofuran (20 mL), copper(II)bromide (19.98 mmol)
was added (Raghunath et al. 2015). The reaction mixture
was allowed to stir at room temperature for 24 h. After
completion of the reaction (monitored by TLC), reaction
mixture was filtered off. The filtrate containing the 2-
bromo-1-phenylethanones 7–12 was taken to the next step
without isolation. However, to check the purity of the
formed phenacyl bromides, two representative compounds
2-Bromo-2’-methoxyacetophenone (8)
1
H NMR (400 MHz, CDCl ): δ 7.82 (dd, J = 1.6 Hz, J =
3
1
2
7.6 Hz, 1H, H-2), 7.52 (dd, J = 2.0 Hz, J = 7.6 Hz, 1H, H-
1
2
6), 7.06 – 6.98 (m, 2H, H-1, H-3), 4.61 (s, 2H, H-8), 3.94 (s,
3H, H-12). m/z (CI): 229.0 (M + 1, 100%). HPLC: 99.2%
[Column: Inertsil ODS 3 V 250 × 4.6 mm, 5 µ; mobile
phase: Acetonitrile:Water (50:50, v/v); Flow rate:
0.6 mL/min; Method: Isocratic flow rate].
(
8 and 10) were isolated in standard procedure by evapor-
ating the solvent under vacuum and confirmed by spectral
1
analysis ( H NMR, Mass, and HPLC). As all the derivatives
3-(2-Bromoacetyl)benzonitrile (10)
were pure by TLC, they were preceded to next step without
purification/isolation.
1
H NMR (400 MHz, CDCl ): δ 8.27 (s, 1H, H-4), 8.22 (d, J
3
=
8.0 Hz, 1H, H-6), 7.90 (d, J = 7.6 Hz, 1H, H-2), 7.66 (t, J
General procedure for synthesis of imidazo[1,2-a]
pyrimidines (14–19)
= 7.6 Hz, 1H, H-1), 4.42 (s, 2H, H-8). m/z (CI): 225.2 (M
+ 1, 100%). HPLC: 99.7% [Column: Inertsil ODS 3 V
250 × 4.6 mm, 5 µ; mobile phase: Acetonitrile:Water (50:50,
To the above filtrate, containing 2-bromo-1-phenylethanones
v/v); Flow rate: 0.6 mL/min; Method: Isocratic flow rate].
7–12 (4.16 g, 21.03 mmol), sodium bicarbonate (8.83 g,
1
05.15 mmol), additional quantity of 2-Me-THF (10 mL),
2-(2-Methoxyphenyl)imidazo[1,2-a]pyrimidine (15)
and 2-aminopyrimidine 13 (2 g, 21.03 mmol) were added
and heated to 85 °C for 10 h in a sealed tube. After com-
pletion of the reaction (monitored by TLC), the mixture was
1
H NMR (400 MHz, DMSO-d ): δ 9.30 (d, J = 5.2 Hz, 1H,
6
H-1), 8.98 (dd, J = 1.6 Hz, J = 4.0 Hz, 1H, H-3), 8.71
1
2

Medicinal Chemistry Research
(
s, 1H, H-7), 8.05 (dd, J = 1.6 Hz, J = 7.6 Hz, 1H, H-15),
1,2-Bis(4-fluorophenyl)-3-(2-methoxyphenyl)-
1
2
7
1
1
1
4
.61 (dd, J = 4.4 Hz, J = 6.8 Hz, 1H, H-2), 7.56-7.52 (m,
2a1,4,5-triazacyclopenta[cd]indene (27)
1
2
H, H-13), 7.30 (d, J = 8.0 Hz, 1H, H-12), 7.21–7.17 (m,
H, H-14), 4.02 (s, 3H, H-17). m/z (CI): 226.0 (M + 1,
00%). HPLC: 99.9% [Column: Inertsil ODS 3 V 250 ×
.6 mm, 5 µ; mobile phase: Acetonitrile:Water (50:50, v/v);
Yellow solid; Yield: 78%; mp: 95-99 °C; IR (KBr) vmax:
3057, 2923, 1705, 1603, 1042, 839, 750 cm ; H NMR
−
1
1
(300 MHz, CDCl ): δ 9.03 (d, J = 5.1 Hz, 1H, H-1), 8.15
3
Flow rate: 0.6 mL/min; Method: Isocratic flow rate].
(dd, J = 1.2 Hz, J = 7.5 Hz, 1H, H-13), 7.79 (d, J =
1
2
5.7 Hz, 1H, H-2), 7.5-7.26 (m, 5H, H-15,20,24,25,29),
3
-(Imidazo[1,2-a]pyrimidin-2-yl)benzonitrile (17)
7.2–7.09 (m, 3H, 21,23,14), 7.0–6.93 (m, 2H, H-26,28),
13
6.78 (d, J = 8.4 Hz, 1H, H-16), 3.01 (s, 3H, H-31);
C
1
H NMR (400 MHz, DMSO-d ): δ 9.00 (d, J = 2.0 Hz, 1H,
NMR (300 MHz, CDCl ): δ 164.4 (C-1), 163.9 (C-3), 161.1
6
3
H-1), 8.58 (dd, J = 2.0 Hz, J = 4.0 Hz, 1H, H-3), 8.53 (s,
(C-5), 160.6 (Ph-C), 156.3 (Ph-C), 153.4 (Ph-C), 147.3 (Ph-
C), 146.8 (Ph-C), 135.2 (Ph-C), 134.9 (Ph-C), 132.7 (Ph-C),
132.3 (Ph-C), 132.0 (Ph-C), 131.9 (Ph-C), 131.6 (Ph-C),
131.4 (Ph-C), 129.98 (Ph-C), 129.94 (Ph-C), 128.8 (Ph-C),
125.3 (Ph-C), 123.8 (Ph-C), 122.3 (Ph-C), 120.98 (Ph-C),
116.26 (Ph-C), 115.9 (Ph-C),115.5 (Ph-C), 115.2 (Ph-C),
1
2
1
1
7
1
H, H-7), 8.44 (t, J = 1.2 Hz, 1H, H-15), 8.35 (td, J =
1
.2 Hz, J = 8.0 Hz, 1H, H-13), 7.84–7.81 (m, 1H, H-12),
2
.69 (t, J = 7.6 Hz, 1H, H-2), 7.10 (d, J = 4.4 Hz, 1H, H-
1). m/z (CI): 221.1 (M + 1, 100%). HPLC: 99.3% [Col-
umn: Inertsil ODS 3 V 250 × 4.6 mm, 5 µ; mobile phase:
Acetonitrile:Water (50:50, v/v); Flow rate: 0.6 mL/min;
Method: Isocratic flow rate].
110.1 (Ph-C), 107.5 (Ph-C), 53.6 (-OCH ); LC-MS: 90%;
3
m/z (CI): 438.4 (M + H, 100%).
1,2,3-Triphenyl-2a1,4,5-triazacyclopenta[cd]indene
Dimethyl 3-(2-methoxyphenyl)-2a1,4,5-
(25)
triazacyclopenta[cd]indene-1,2-dicarboxylate (28)
Yellow solid; Yield: 76%; mp: 198-200 °C; IR (KBr) vmax:
Yellow solid; Yield: 74%; mp: 175-180 °C; IR (KBr) v
3546, 2864, 1641, 1535, 1459, 1091, 980, 818 cm ; H
:
max
1
−1
1
−1
3051, 2920, 1708, 1537, 1046, 818, 717 cm ; H NMR
(
300 MHz, CDCl ): δ 9.05 (d, J = 5.4 Hz, 1H, H-1),
NMR (400 MHz, CDCl ):δ 9.04 (m, 1H, H-1), 8.34 (d, J =
3
3
7
1
1
.93–7.89 (m, 3H, H-2, 13 and 17), 7.48-7.28 (m, 13H, H-14-
6.8 Hz, 1H, H-19), 8.17 (d, J = 5.2 Hz, 1H, H-2), 7.56
(t, J = 7.2 Hz, 1H, H-21), 7.19 (t, J = 7.6 Hz, 1H, H-20),
7.09 (d, J = 8.4 Hz, 1H, H-22), 4.00 (s, 3H, H-26), 3.97 (s,
13
6, H-20-29); C NMR (300 MHz, CDCl ): δ 157.1 (C-1),
3
47.5 (C-3), 147.2 (C-5), 136.0 (Ph-C), 134.9 (Ph-C), 133.2
1
3
(C-10), 132.8 (C-11), 132.7 (Ph-C), 130.65 (Ph-C), 130.14
Ph-C), 130.0 (Ph-C), 129.7 (Ph-C), 128.9 (Ph-C), 128.8 (Ph-
3H, H-27), 3.88 (s, 3H, H-25); C NMR (400 MHz,
(
CDCl ): δ 174.2 (C-1), 164.1 (C-3), 163.03 (Ph-C), 157.5
3
C), 128.5 (Ph-C), 128.4 (Ph-C), 127.4 (Ph-C), 108.19 (Ph-C);
LC-MS: 88%; m/z (CI): 372.33 (M + H, 100%).
(C-5), 148.5 (Ph-C), 133.5 (Ph-C), 133.4 (Ph-C), 132.5 (Ph-
C), 130.6 (Ph-C), 121.6 (Ph-C), 116.1(Ph-C), 111.4 (Ph-C),
1
10.8 (Ph-C), 56.15 (-OCH ), 52.8 (-OCH ), 52.3 (-OCH );
3 3 3
3-(2-Methoxyphenyl)-1,2-diphenyl-2a1,4,5-
LC-MS: 95.4%; m/z (CI): 366 (M + H, 100%).
triazacyclopenta[cd]indene (26)
Dimethyl 3-(4-methoxyphenyl)-2a1,4,5-
triazacyclopenta[cd]indene-1,2-dicarboxylate (29)
Bright yellow solid; Yield: 72%; mp: 259-266 °C; IR (KBr)
vmax: 2956, 2852, 1897, 1719, 1406, 1171, 918 cm ; H
−1
1
NMR (400 MHz, DMSO-d ):δ 9.03 (d, J = 6.0 Hz, 1H, H-
Bright yellow solid; Yield: 70%; mp: 183-185 °C; IR (KBr)
vmax: 3567, 2853, 1604, 1088, 972, 813 cm ; H NMR
6
−
1
1
1
), 8.08 (d, J = 5.2 Hz, 1H, H-2), 7.97 (dd, J = 1.6 Hz, J
1
2
=
7.6 Hz, 1H, H-13), 7.51 (t, J = 8.8 Hz, 1H, H-15),
(400 MHz, CDCl ): δ 9.04 (d, J = 5.6 Hz, 1H, H-1), 8.25 (d,
3
7
1
.43–7.22 (m, 10H, H-20-29), 7.13 (t, J = 7.2 Hz, 1H, H-
J = 8.8 Hz, 2H, H-19,23), 8.11 (d, J = 6.0 Hz, 1H, H-2),
7.09 (d, J = 8.8 Hz, 2H, H-20,22), 4.12 (s, 3H, H-26), 4.03
(s, 3H, H-27), 3.92 (s, 3H, H-25); C NMR (400 MHz,
1
3
4), 6.9 (d, J = 8.4 Hz, 1H, H-16), 2.8 (s, 3H, H-31);
C
1
3
NMR (400 MHz, DMSO-d ): δ 156.1 (C-1), 152.4 (C-3),
6
1
1
1
1
1
5
47.0 (Ph-C), 146.6 (Ph-C), 135.6 (Ph-C), 134.0 (Ph-C),
33.0 (Ph-C), 132.4 (Ph-C), 132.1 (Ph-C), 131.6 (Ph-C),
29.67 (Ph-C), 129.62 (Ph-C), 128.8 (Ph-C), 128.4 (Ph-C),
28.29 (Ph-C), 127.5 (Ph-C), 125.9 (Ph-C), 123.4 (Ph-C),
22.0 (Ph-C), 120.4 (Ph-C), 110.7 (Ph-C), 108.4 (Ph-C),
CDCl ): δ 165.3 (C-1), 163.2 (C-3), 163.0 (C-5), 160.9 (Ph-
3
C), 149.0 (Ph-C), 148.7 (Ph-C), 133.0 (Ph-C), 131.0 (Ph-C),
129.0 (Ph-C), 124.0 (Ph-C), 120.4 (Ph-C), 115.6 (Ph-C),
114.8 (Ph-C), 110.4 (Ph-C), 55.5 (-OCH ), 53.5 (-OCH ),
3
3
52.3(-OCH ); LC-MS: 99.9%; m/z (CI): 366.2 (M +
3
3.4 (-OCH ); LCMS: 99%; m/z (CI): 402.4 (M + H 100%).
H, 100%).
3

Medicinal Chemistry Research
3
-(1,2-Bis(4-fluorophenyl)-2a1,4,5-triazacyclopenta
4-(1,2-Di-p-tolyl-2a1,4,5-triazacyclopenta[cd]inden-
3-yl)benzonitrile (33)
[cd]inden-3-yl)benzonitrile (30)
Bright yellow solid; Yield: 61%; mp: 275-279°C; IR (KBr)
vmax: 3061, 2854, 2227, 1514, 1234, 1143, 860 cm ; H
Yellow solid; Yield: 68%; mp: 256-258 °C; IR (KBr) vmax:
3453, 2746, 2227, 1888, 1538, 815, 697 cm ; H NMR
−
1
1
−1
1
NMR (400 MHz, CDCl ):δ 9.08 (d, J = 5.2 Hz, 1H, H-1),
(400 MHz, CDCl ): δ 9.11 (d, J = 4.8 Hz, 1H, H-1), 8.02 (d,
3
3
7
.93 (d, J = 8.4 Hz, 2H, H-17,15), 7.83 (d, J = 5.6 Hz, 1H,
H-2), 7.49-7.31 (m, 6H, H-16,19,20,24,25,29), 7.17–7.08
m, 4H, H-21,23,26,28); 13C NMR (400 MHz, CDCl ): δ
66.8 (Ph-C), 164.7 (Ph-C), 164.3 (Ph-C), 150.5 (Ph-C),
42.9 (Ph-C), 140.2 (Ph-C), 136.5 (Ph-C), 135.9 (Ph-C),
35.02 (Ph-C), 135.00 (Ph-C), 134.99 (Ph-C), 134.9 (Ph-
J = 8.4 Hz, 2H, H-25,29), 7.91 (d, J = 3.2 Hz, 1H, H-2), 7.6
(d, J = 8.0 Hz, 2H, H-26,28), 7.32–7.22 (m, 8H, H-
15,16,18,19,20,21,23,24), 2.47 (s, 3H, H-32), 2.39 (s, 3H,
(
3
1
3
1
1
1
H-33); C NMR (400 MHz, CDCl ): δ 153.28 (C-1),
3
148.23 (C-3), 147.09 (C-5), 139.3 (Ph-C), 137.7 (Ph-C),
137.1 (Ph-C), 136.0 (Ph-C), 132.1 (Ph-C), 130.4 (Ph-C),
130.3 (Ph-C), 129.9 (Ph-C), 129.7 (Ph-C), 129.7 (Ph-C),
129.6 (Ph-C), 128.6 (Ph-C), 123.4 (Ph-C), 118.6 (Ph-C),
113.4 (Ph-C), 108.8 (Ph-C), 21.4 (CH ), 21.2 (CH ); LC-
C), 133.8 (Ph-C), 122.3 (Ph-C), 121.6 (Ph-C), 119.8 (Ph-C),
17.2 (Ph-C), 116.9 (Ph-C); LC-MS: 96%; m/z (CI): 433.3
M + H, 100%).
1
(
3
3
MS: 97%; m/z (CI): 425.4 (M+H, 100%).
3
3
-(1,2-Diphenyl-2a1,4,5-triazacyclopenta[cd]inden-
-yl)benzonitrile (31)
3-(2-Nitrophenyl)-1,2-diphenyl-2a1,4,5-
triazacyclopenta[cd]indene (34)
Orange solid; Yield: 82%; mp: 253-256 °C; IR (KBr) vmax:
−
1
1
3
410, 3062, 2228, 1850, 1695, 965, 854 cm ; H NMR
Pale green solid; Yield: 64%; mp: >400 °C; IR (KBr)
: 3068, 2925, 2812, 1750, 1624, 986, 865, 810 cm−
1
;
(
400 MHz, CDCl ):δ 9.1 (d, J = 5.2 Hz, 1H, H-1), 8.26 (d,
v
3
max
1
J = 8.0 Hz, 1H, H-17), 8.0 (s, 1H, H-19), 7.94 (d, J =
H NMR (400 MHz, CDCl ): δ 8.68 (q, J = 2.1 Hz, 1H,
3
5
.2 Hz, 1H, H-2), 7.64 (d, J = 8.0 Hz, 1H, H-15), 7.58–7.54
H-1), 7.79 (m, 2H, H-2,18), 7.55 (d, J = 7.8 Hz, 1H, H-
17), 7.45 (dd, J = 1.8 Hz, J = 6.9 Hz, 1H, H-16),
7.41–7.32 (m, 3H, H-15,20,24), 7.3-7.23 (m, 5H, 21, 23,
(
(
m, 1H, H-16), 7.5–7.33 (m, 10H, H-20-29); 13C NMR
1
2
400 MHz, CDCl ): δ 153.3 (C-1), 148.8 (C-3), 147.1 (Ph-
3
C), 135.9 (Ph-C), 135.6 (Ph-C), 134.0 (Ph-C), 133.6 (C-10),
25, 29, 26), 7.2-7.16 (m, 2H, H-22,28), 6.6 (q, J =
1
3
1
1
1
1
33.4 (C-11), 133.4 (Ph-C), 132.8 (Ph-C), 132.4 (Ph-C),
30.2 (Ph-C), 129.7 (Ph-C), 129.6 (Ph-C), 129.4 (Ph-C),
29.1 (Ph-C), 128.9 (Ph-C), 128.3 (Ph-C), 127.7 (Ph-C),
23.2 (Ph-C), 117.9 (C-30), 112.8 (Ph-C), 108.8 (Ph-C);
3.9 Hz, 1H, H-27); C NMR (400 MHz, CDCl ): δ 161.8
3
(C-1), 150.0 (C-3), 147 (Ph-C), 141.3 (Ph-C), 136.7 (Ph-
C), 134.4 (Ph-C), 133.4 (Ph-C), 133.2 (Ph-C), 130.4 (Ph-
C), 129.2 (Ph-C), 128.9 (Ph-C), 128.6 (Ph-C), 128.3 (Ph-
C), 127.2 (Ph-C), 124.1 (Ph-C), 123.4 (Ph-C), 118.82
LC-MS: 99.5%; m/z (CI): 397.4 (M + H, 100%).
(
Ph-C), 116.4 (Ph-C), 113.7 (Ph-C); LC-MS: 95%; m/z
3
-(1,2-Di(pyridin-2-yl)-2a1,4,5-triazacyclopenta[cd]
(CI): 417.14 (M + H, 100%).
inden-3-yl)benzonitrile (32)
3-(4-methoxyphenyl)-1,2-diphenyl-2a1,4,5-
Yellow solid; Yield: 65%; mp: 173-177 °C; IR (KBr) vmax:
triazacyclopenta[cd]indene (35)
−
1
1
3
433, 3062, 2228, 1584, 1066, 771, 683 cm ; H NMR
(
400 MHz, CDCl ): δ 9.17 (s, 1H, H-1), 8.96 (s, 1H, H-23),
Bright yellow solid; Yield: 74%; mp: 249-251 °C; IR (KBr)
3
8
.7 (s, 1H, H-26), 8.47-8.39 (m, 2H, H-21,28), 8.03 (s, 1H,
vmax: IR: 3439, 2922, 2562, 1732, 1604, 1256, 1027,
−
1 1
H-2), 7.87 (m, 1H, H-15), 7.68 (d, J = 8.0 Hz, 1H, H-17),
747 cm ; H NMR (400 MHz, CDCl ) δ 8.99 (s, 1H, H-1),
3
7
7
.58–7.49 (m, 4H, H-27,29,20,22,), 7.23 (m, 1H, H-16),
.13 (d, J = 7.2 Hz, 1H, H-19); C NMR (400 MHz,
7.9 (d, J = 6.0 Hz, 2H, H-25,29), 7.83 (d, J = 2.8 Hz, 1H,
H-2), 7.49–7.29 (m, 10H, H-15-24), 6.8 (d, J = 12 Hz, 2H,
H-26,28), 3.8 (s, 3H, H-31); C NMR: (400 MHz, CDCl3)
δ 161.8 (C-1), 147.8 (C-3), 146.8 (C-5), 135.6 (Ph-C),
134.4 (Ph-C), 133.5 (Ph-C), 133.0 (Ph-C), 131.7 (Ph-C),
130.6 (Ph-C), 129.7 (Ph-C), 128.8 (Ph-C), 128.7 (Ph-C),
127.3 (Ph-C), 127.0 (Ph-C), 125.4 (Ph-C), 113.9 (Ph-C),
13
1
3
CDCl ): δ 154.3 (C-1), 152.7 (C-3), 152.3 (C-5), 150.7 (Ph-
C), 150.2 (Ph-C), 148.7 (Ph-C), 137.2 (Ph-C), 136.3 (Ph-C),
3
1
1
1
1
35.7 (Ph-C), 134.4 (Ph-C), 134.0 (Ph-C), 133.6 (Ph-C),
33.4 (Ph-C), 129.4 (Ph-C), 128.3 (Ph-C), 125.9 (Ph-C),
24.4 (Ph-C), 123.4 (Ph-C), 123.2 (Ph-C), 122.2 (Ph-C),
18.1 (Ph-C), 112.6 (Ph-C), 112.0 (Ph-C), 29.59 (-OCH3);
107.8 (Ph-C), 55.7 (-OCH ); LCMS: 99.9%; m/z (CI) 402.4
3
LC-MS: 93%; m/z (CI): 399.1 (M + H, 100%).
(M + H, 100%).

Medicinal Chemistry Research
Scheme 1 Synthesis of 1,2-3-
substituted-2a1,4,5-
triazacyclopenta[cd]indene 25–
36 Reaction conditions: a CuBr,
2-Me-THF, room temperature,
24 h; b NaHCO3, 2-Me-THF, 2-
aminopyrimidine, 85 °C, 10 h; c
Pd(OAc)2, Cu(OAc)2, TBAB,
DMF, 90 °C, 12 h
3
-(4-methoxyphenyl)-1,2-di-p-tolyl-2a1,4,5-
2a1,4,5-triazacyclopenta[cd]indenes 25–36. Paw edema
was induced by injecting 0.1 mL of 1% w/v carrageenan
suspended in 1% CMC into sub-plantar tissues of the left
hind paw of each rat. The paw thickness was measured
before injecting the carrageenan and after 60, 120, 180 min
using Vernier callipers. The anti-inflammatory activity was
calculated as percentage inhibition of edema in the animals
treated with compounds 25–36 in comparison to the carra-
geenan control group. The study was carried out as per the
protocols approved by the Institutional Animal Ethical
Committee (IAEC) of CPCSEA (Committee for the Purpose
of Control and Supervision of Experiments on Animals).
The animals were starved overnight and administered with
Diclofenac sodium (standard drug) at dose of 10 mg/kg and
test compounds (25–36, 10 mg/kg i.p), were controlled
orally using gastric canula, 30 min before the carrageenan
injection in sub-plantar region of left hind paw.
triazacyclopenta[cd]indene (36)
Bright yellow solid; Yield: 65%; mp: 186-189 °C; IR (KBr)
vmax: 3510, 3018, 1675, 1173, 879, 627 cm ; H NMR
−
1
1
(
400 MHz, CDCl ):δ 8.96 (d, J = 5.6 Hz, 1H, H-1), 7.93 (d,
3
J = 8.8, 2H, H-25,29), 7.8 (d, J = 5.6, 1H, H-2), 7.35–7.21
m, 8H, H-15,16,18,19,20,21,23,24), 6.83 (d, J = 8.8 Hz,
H, H-26,28), 3.85 (s, 3H, H-33), 2.45 (s, 3H, H-32), 2.38
(
2
1
3
(
s, 3H, H-31); C NMR (400 MHz, CDCl ): δ 161.7 (Ph-
3
C), 157.0 (Ph-C), 147.7 (Ph-C), 146.7 (Ph-C), 138.6 (Ph-C),
1
1
1
1
2
37.1 (Ph-C), 135.6 (Ph-C), 134.6 (Ph-C), 131.7 (Ph-C),
30.5 (Ph-C), 130.4 (Ph-C), 130.2 (Ph-C), 129.5 (Ph-C),
29.4 (Ph-C), 126.9 (Ph-C), 125.6 (Ph-C), 122.5 (Ph-C),
13.9 (Ph-C), 107.6 (Ph-C), 55.4 (-OCH ), 21.5 (-CH ),
3
3
1.2 (-CH ); LCMS: 99%; m/z (CI) 430.4 (M + H, 100%).
3
Experimental section for the evaluation of anti-
inflammatory activity
The percentage (%) inhibition of edema was calculated
using the formula
%
inhibition ¼ To À Tt=To  100
Carrageenan induced paw edema test method (Winter et al.
1
2
962; Kumar Reddy, Niren 2017; Kumar Reddy, Niren
016) (Wistar rats) was adopted for the evaluation of anti-
Where T is the thickness of paw of rats administered test
t
extract at corresponding time and T is the paw thickness of
o
inflammatory activity for the synthesized 1,2-3-substituted-
rats of control group at the same time. The results of 0 h

Medicinal Chemistry Research
Fig. 1 Plausible reaction
mechanism
control sample and Diclofenac standard drug administration
and 3 h after dosage administration are illustrated in Fig. 3
and Fig. 4, respectively.
conditions led to the exclusive formation of 1,2-3-sub-
stituted 2a1,4,5-triazacyclopenta[cd]indene derivatives
25–36 exclusively rather than the formation of the fused
tetra cyclic ring system (Sanjay et al. 2016). The acetylenes
20 and 21 are commercially available, while the remaining
Results and discussion
acetylenes 22–24 were prepared according to the reported
literature procedures. (Norio et al. 2010; Manashi et al.
2016; Ulrik, Pombo-Villar 2005).
Chemistry
The investigation into the plausible reaction mechanism
for the exclusive formation of these derivatives is based on
the previous literature a plausible reaction mechanism for
these dehydrogenative annulations is outlined above. Pos-
sibly the initial formation of the active intermediate A is
formed through electrophilic palladation at the 3-position of
imidazopyrimidine moiety and the resulting intermediate A
inserts into biphenylalkyne to produce a vinylicpalladium
(II) intermediate B. Subsequently this intermediate B pro-
duces six-membered palladacycle C through C–H activa-
tion. Finally the Intermediate C afforded the corresponding
2,3,4-triarylphenyl-1,7b-triaza-cyclopenta[cd]indene deri-
vative via reductive elimination along with the generation of
Pd(0). This Pd(0) is reoxidized to the Pd(II) species by Cu
(OAc) .H O to complete the catalytic cycle as represented
The synthesis of 1,2,3-substituted-2a1,4,5-triazacyclopenta
[
cd]indene 25–36 is illustrated in (Scheme 1). Bromination
of acetophenones 1–6 in presence of copper(II)bromide in
-Me-tetrahydrofuran at room temperature for 12 h pro-
duced the corresponding acyl bromides (Raghunath et al.,
015) 7–12. For Bromination, CuBr was found to be a
2
2
2
versatile reagent, as well as a clean process when compared
to the usage of the liquid bromine for the preparation of
acylbromides. Condensation of 2-bromo-1-(substituted
phenyl)ethanones 7–12 with 2-aminopyrimidine in presence
of sodium bicarbonate in 2-Me-tetrahydrofuran in sealed
tube at 85 °C for 10 h resulted in the formation of various
corresponding imidazo[1,2-a]pyrimidines 14–19. These
compounds when treated with 1,2-diaryl/diaklylethynes
2
2
2
0–24 in presence of Pd(OAc) , Cu(OAc) and TBAB in
in Fig. 1.
2
2
DMF:PEG-1500 in sealed tube at 90 °C for 12 h resulted in
the formation of the 1,2-3-substituted 2a1,4,5-triazacyclo-
penta[cd]indene derivatives 25–36 in good to excellent
yields. It is worth mentioning that the above reaction
The structural elucidation of these derivatives has been
performed by H NMR, C NMR, LC-MS, and IR spec-
troscopy. As a representative sample, 3-(1,2-Diphenyl-
1
13
2a1,4,5-triazacyclopenta[cd]inden-3-yl)benzonitrile
(31)

Medicinal Chemistry Research
Fig. 2 1H– C gHMBC
spectrum, key correlations
shown with red colored circles
and also key proton and carbons
numbering given (color figure
online)
13
was completely characterized. We have performed proton
and carbon NMR to know number of proton and carbon
atoms, and also for chemical shifts, respectively. Dis-
135.60 ppm in gHMBC data (Fig. 2). The presence of only
two protons on pyrimidine ring and C10 correlation with
phenyl ring protons and H2 confirms that the cyclisation has
happened on pyrimidine ring. Thus the above spectroscopic
description confirms the structure of compound 31. Simi-
larly, the remaining compounds in the series are in agree-
ment with the desired structure.
tortionless Enhancement by Polarization Transfer (DEPT-
0
1
35 ) to find out number of protonated carbons and its type,
gradient proton–proton correlation spectroscopy (gCOSY)
Fig. 2) to know the information about adjacent coupled
(
partners (protons), gradient hetero nuclear single quantum
1
coherence spectroscopy (gHSQC) to know about J corre-
Anti-inflammatory activity
lation between proton and carbon (which proton is attached
to which carbon), gradient hetero nuclear multiple bond
Table 1 illustrates the results of the anti-inflammatory
activity of the above synthesized compounds 25-36. Com-
pounds 28 (R = 2-methoxy, R’ = Phenyl), 30 (R = 3-CN,
3
correlation spectroscopy (gHMBC) (Fig. 1) to know the J
3
correlations between proton and carbons. Other than J
2
4
couplings, J and J were also observed in gHMBC data
Fig. 1). The N15 HMBC experimental data revealed the
R’ = 4-F-Phenyl), 33 (R = 4-CN, R’ = 4-CH -Phenyl) and
3
(
35 (R = 4-methoxy, R’ = Phenyl) exhibited good anti-
inflammatory activity with 68%, 68.8%, 68%, and 68.4%
inhibition, respectively (w.r.t. Diclofenac sodium, 71.1%
inhibition). Figure 4 shows the control group rat paw,
Diclofenac administered rat paw, and compound 30 and 35
administered rat paw images at 0 h. Figure 5 shows the
control group rat paw, Diclofenac administered rat paw, and
compound 30 and 35 administered rat paw images after 3 h.
Compounds 26 (R = 2-methoxy, R’ = Phenyl), 31 (R = 3-
chemical shifts of pyrimidine ring nitrogen.
There are 16 protons detected in aromatic region of
proton NMR as based on integration, out of which two of
the protons signals resonating at 9.10 ppm and 7.94 ppm as
doublets with coupling constant (J) of 4.0 Hz are assigned
to pyrimidine ring protons. The splitting pattern of four
proton signals resonating at 8.20 ppm (doublet of triplet),
8
7
.00 ppm (weak triplet), 7.66 ppm (doublet of triplet), and
.46 ppm (strong triplet) confirms the presence of 1, 3-
CN, R’ = Phenyl) and 34 (R = 2-NO , R’ = Phenyl),
2
disubstituted benzene ring (3-cyano phenyl ring), which is
merged in phenyl ring protons and its presence is confirmed
by gCOSY (Fig. 3) experimental data. Presence of cyano
group is confirmed by the correlation between H17 and H19
to C30 in gHMBC (Fig. 2) data and its carbon value is at
showed moderate anti-inflammatory activity with 66.6%,
66.6%, 67.1% inhibition while compounds 25 (R = H,
R’ = Phenyl), 27 (R = 2-methoxy, R’ = 4-F-Phenyl), 29 (R
= 4-methoxy, R’ = CO CH ), 32 (R = 3-CN, R’ = 3-Pyr-
2
3
idyl) and 36 (R = 4-methoxy, R’ = 4-CH -Phenyl) dis-
3
1
17.9 ppm. Ortho protons of one of the phenyl ring (H25
played weak anti-inflammatory activity with 63.5%, 64.4%,
and H29) and H2 were showing 3J correlation with C10 at
62.2%, 63.4%, 65.3% inhibition.

Medicinal Chemistry Research
Fig. 3 1H– H COSY spectrum of compound 31, H1, H2 proton cor-
relation belongs to pyrimidine ring; H17, H19, H15, and H16 corre-
lations belongs to 3-cyano phenyl ring; red colored dotted box
1
indicates the correlation of two phenyl rings which are overlapped
together (color figure online)
Table 1 Anti-inflammatory
activity of 1,2-3-substituted-
Treatments
60 min
120 min
180 min
Percentage of inhibition
at 180 min
2
a1,4,5-triazacyclopenta[cd]
indenes 25–36
Carrageenan control
1.4 ± 0.04
1.85 ± 0.064
2.25 ± 0.06
–
2
2
2
2
2
3
3
3
3
3
3
3
5
6
7
8
9
0
1
2
3
4
5
6
1.110 ± 0.02*** 1.255 ± 0.044*** 0.82 ± 0.03*** 63.5
1.18 ± 0.03*** 1.115 ± 0.020*** 0.72 ± 0.028*** 66.6
1.15 ± 0.08***
1.22 ± 0.06***
1.18 ± 0.035*** 0.72 ± 0.025*** 68.0
0.85 ± 0.02*** 62.2
0.80 ± 0.04*** 64.4
1.22 ± 0.04***
1.175 ± 0.06*** 1.375 ± 0.02***
1.025 ± 0.058*** 0.82 ± 0.056*** 0.70 ± 0.004*** 68.8
1.2 ± 0.04*** 1.225 ± 0.025*** 0.75 ± 0.02*** 66.6
1.175 ± 0.04***
1.2 ± 0.04*** 0.822 ± 0.25*** 63.4
1.045 ± 0.062*** 0.87 ± 0.067*** 0.72 ± 0.003*** 68.0
0.90 ± 0.08***
1.1 ± 0.08***
0.81 ± 0.02***
0.74 ± 0.06*** 67.1
0.97 ± 0.047*** 0.71 ± 0.002*** 68.4
1.075 ± 0.06***
0.92 ± 0.025***
0.8 ± 0.04***
0.78 ± 0.002*** 65.3
Diclofenac sodium
10 mg/kg)
0.8 ± 0.04***
0.65 ± 0.02*** 71.1
(
Note: Values are expressed as mean ± S.E.M of 4 animals. Superscript letters represent the statistical
significance done by ANOVA, followed by Tukey’s multiple comparison tests. * P < 0.001, P < 0.01, P
0.05 indicates comparison of with control group with negative control and negative control with
treatment groups
**
**
*
<
Conclusion
Carrageenan induced paw edema test method in which they
showed comparable anti-inflammatory activity against the
drug Diclofenac sodium. Compounds 28 (R = 2-methoxy,
R’ = Phenyl), 30 (R = 3-CN, R’ = 4-F-Phenyl), 33 (R = 4-
In conclusion, the present study describes the synthesis of
some novel 1,2-3-substituted-2a1,4,5-triazacyclopenta[cd]
indene derivatives 25–36. These derivatives were char-
CN, R’ = 4-CH -Phenyl), and 35 (R = 4-methoxy, R’ =
3
1
acterized by H NMR, Mass, and IR spectral data and were
Phenyl) exhibited good anti-inflammatory activity with
further evaluated for anti-inflammatory activity using
68%, 68.8%, 68%, and 68.4% inhibition, respectively

Medicinal Chemistry Research
Acknowledgements SS is thankful to Department of Chemistry,
Jawaharlal Nehru Technological University, Hyderabad, Telangana,
India, for helpful suggestions and constant encouragement.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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