Copper-mediated domino synthesis of pyrimido[4,5-b]carbazolones via Ullmann N-arylation and aerobic oxidative C-H amidation

Article abstract of DOI:10.1039/c2ob07179g

New pyrimido[4,5-b]carbazolone derivatives have been synthesized through cascade Ullmann N-arylation and aerobic oxidative C-H amidation reactions catalyzed by CuBr under air and ligand-free conditions.

Full text of DOI:10.1039/c2ob07179g

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PAPER
Copper-mediated domino synthesis of pyrimido[4,5-b]carbazolones via
Ullmann N-arylation and aerobic oxidative C–H amidation†
Devanga K. Sreenivas, Nagarajan Ramkumar and Rajagopal Nagarajan*
Received 26th December 2011, Accepted 20th February 2012
DOI: 10.1039/c2ob07179g
New pyrimido[4,5-b]carbazolone derivatives have been synthesized through cascade Ullmann N-arylation
and aerobic oxidative C–H amidation reactions catalyzed by CuBr under air and ligand-free conditions.
fundamental mechanism of C–H activation.10 The domino reac-
tion has thus emerged as a powerful tool for constructing
Introduction
Carbazoles are interesting structural scaffolds of a vast number
of biologically active natural and unnatural compounds that are
known for their potent biological activities (e.g., cytotoxic, anti-
tumor, antibiotic, antiviral and anti-oxidative activities).1–4 Car-
bazole and its derivatives are also widely used as organic
materials due to their photo-physical properties.2 The syntheses
and functionalization of carbazoles has been the main object of
much research over the years and makes them privileged struc-
tures in drug design and development. Considering the impor-
tance of its role in drug design, it is more valuable to synthesize
new carbazole derivatives containing fused pyrimidine ring.3 A
variety of fused N-heterocycles exhibit a number of useful bio-
logical and pharmacological activities (Fig. 1).4 The structurally
related heteroaryl annulated carbazole,14 ellipticine (5,11-
dimethyl-6H-pyrido[4,3-b]carbazole)4 (Fig. 1) and its derivatives
are known for their high anti-cancer, anti-HIV and DNA inter-
calating activities where a variety of well-established synthetic
methods have been reported.5 One of the possible approaches to
new ellipticine analogues was the modification of pyridine
moiety (ring D) of the tetracyclic skeleton by replacement with
other heterocycles producing benzo-, pyrrolo-, pyrazino-,
pyrano-, imidazo-, indolo-, furo-, and thieno-carbazoles has been
described in the literature.6,7
complex molecules from readily available building blocks in
which a series of chemical reactions can be controlled in a par-
ticular step.11 Hence, copper-catalyzed domino reactions are
very useful for constructing various N-heterocycles.12 We herein
report a facile synthesis of new pyrimido[4,5-b]carbazolone
derivatives through cascade Ullmann N-arylation and aerobic
oxidative C–H amidation reactions catalyzed by CuBr under air
and ligand-free conditions.
Results and discussion
A new route to pyrimidine ring formation, starting from substi-
tuted 2-bromo-9H-carbazole-3-carboxamides 3a–e (Scheme 1)
which can be readily prepared from the corresponding aldehydes
1a–e.13 Initially, 2-bromo-9-ethyl-6-methyl-9H-carbazole-3-car-
boxamide 3a and benzylamine 4a were used as the model sub-
strates to optimize reaction conditions including catalysts, bases,
solvents, and reaction temperatures under air (1 atm). As shown
in Table 1, five copper salts (0.01 mmol) were tested with 4.0
A great deal of studies have been directed towards the use of
copper salts in the synthesis and functionalization of hetero-
cycles.8 Recent progress in modern copper-mediated Ullmann
coupling reactions has led to emergence of numerous methods to
condense aryl halides with amines.9 Oxidative insertion reactions
into saturated C–H bonds to form amines or amine derivatives
using copper salts are attractive synthetic methodologies and
these reactions also offer opportunities to understand the
School of Chemistry, University of Hyderabad, Hyderabad-500 046,
India. E-mail: rnsc@uohyd.ernet.in; Fax: +91 40-23012460
†Electronic supplementary information (ESI) available: Spectral data,
LC-MS, elemental analysis for all the compounds synthesized, as well
as absorption and emission data for compounds 5a, 5i and 8a. See DOI:
10.1039/c2ob07179g
Fig. 1 Examples of some fused N-heterocycles.
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of reactivity was observed for the examined substituted 2-bromo-
9H-carbazole-3-carboxamides and (aryl)methanamines with
varied electronic properties, including electron-rich, electron-
poor, and neutral substrates. The copper-mediated domino syn-
thesis of pyrimido[4,5-b]carbazolones could tolerate various
functional groups including ether (entry 2 of Table 2), C–Cl and
C–F bonds (entries 4 and 5 of Table 2) and heterocyclic ring
containing oxygen and sulphur (entries 6 and 9–10 of Table 2)
in the (aryl)methanamines.
Scheme 1 Synthesis of 3a–e.
A possible mechanism for synthesis of pyrimido[4,5-b]carba-
zolone derivatives is proposed in Scheme 2 according to the
results above. Copper-catalyzed Ullmann-type coupling of sub-
stituted 2-bromo-9H-carbazole-3-carboxamides with (aryl)
methanamine provides a N-arylation product (I). Surprisingly, no
ligand or additive was required in the reaction system, and the
result showed an ortho-substituent effect of the amide group in 3
during N-arylation. Copper catalyzed aerobic oxidation of I
affords intermediate II containing a CvN bond, and intramole-
cular nucleophilic addition of the amide to the CvN bond in II
gives III. Finally, further aerobic oxidation of III provides the
target compound 5.
We have also synthesized fused pyrimido[4,5-b]carbazolones
from substituted 2-bromo-9H-carbazole-3-carbonyl chlorides
6a–b and pyridin-2-amine 7 using CuI as a catalyst (Scheme 3).
We herein used Pd(OAc)2 as a co-catalyst to form in situ amide
from the corresponding acid chlorides and amine followed by
intramolecular Ullmann-type N-arylation led to the desired pro-
ducts 8a–b due to ortho-substituent effect of pyridine group.12
The reaction was carried out with K2CO3 as the base, toluene as
a solvent under nitrogen atmosphere at 110 °C for 10 h.
Table 1 Optimisation of reaction conditionsa
Temp (°C)/ Yieldb
Entry Catalyst
Base
Solvent
time (h)
(%)
1
2
3
4
5
6
CuCI
CuO
CuO
Cu(OAc)2 K2CO3
CuI
K2CO3
K2CO3
AcONa
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120/3
120/3
120/3
120/3
120/3
120/6
120/13
120/3
120/3
120/3
120/8
120/3
110/3
0
Trace
0
20
63
71
67
78
73
33
22
54
18
27
Trace
0
K2CO3
Cs2CO3
CuI
7
8
9
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Na2CO3 DMSO
K2CO3
Cs2CO3
K3PO4
DMSO
DMSO
DMSO
10
11
12
13
14
15
16
17
18
19
20
DABCO DMSO
t-BuOK DMSO
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
Ethylene glycol 120/3
NMP
DMSO
DMSO
DMSO
DMSO
DMSO
120/3
70/2
Conclusion
90/6
47
66
13c
54d
In conclusion, we have synthesized a series of pyrimido[4,5-b]-
carbazolone derivatives using cascade Ullmann N-arylation and
aerobic oxidative C–H amidation reactions that allow the assem-
bly of readily accessible building blocks into diverse (heteroaryl-
annulated) pyrimido[4,5-b]carbazolones with the aid of CuBr as
a catalyst without any additives or ligands. An attractive feature
of this synthetic approach is not only to provide a new approach
for constructing pyrimido[b]carbazoles but also offers an
efficient method for preparation of synthetically and medicinally
important hetero-arylated carbazoles. Furthermore, some of the
resulting pyrimido[4,5-b]carbazolone derivatives exhibit intense
fluorescence (see ESI†).
110/5
120/24
120/3
a Reaction
conditions:
2-bromo-9-ethyl-6-methyl-9H-carbazole-3-
carboxamide 3a (0.2 mmol), benzylamine 4a (0.24 mmol), catalyst
(0.01 mmol), base (0.8 mmol), solvent (3.0 mL) under air. b Isolated
yield. c Under nitrogen balloon. d Under oxygen balloon.
equiv. of K2CO3 relative to amount of 3a as a base and DMSO
as the solvent at 120 °C (entries 1, 3–5 and 7), and CuBr pro-
vided the better yield (entry 8). Other bases, Na2CO3, Cs2CO3,
K3PO4, DABCO and t-BuOK (entries 7 and 9–12), were
screened, and K2CO3 showed the best activity (compare entries
8, 7 and 9–12). The effect of solvents was also examined; and
DMSO was the optimal solvent (compare entries 8 and 13–15).
We attempted different reaction temperatures (entries 16–18),
and 120 °C was the best choice. The scope of copper-catalyzed
domino reactions of substituted 2-bromo-9H-carbazole-3-carbox-
amides with (aryl)methanamines was investigated under the opti-
mized conditions using 10 mol% of CuBr as the catalyst, 4.0
equiv. of K2CO3 as the base, and DMSO as the solvent. As
shown in Table 2, most of the substrates examined provided
good yields at 120–130 °C. In general, no significant difference
Experimental section
General information
Column chromatography was performed on silica gel
(100–200 mesh) in glass columns to purify all the compounds
using ethyl acetate–hexane as eluent. All reactions were carried
out under air and monitored by TLC. Proton and carbon mag-
netic resonance spectra (1H NMR and 13C NMR) were recorded
on a Bruker AV-400 spectrometer operating at 400 and 100 MHz
respectively, using tetramethylsilane (TMS) in the solvent of
CDCl3 as the internal standard (1H NMR: TMS at 0.00 ppm,
CDCl3 at 7.26 ppm; 13C NMR: CDCl3 at 77.4 ppm) or were
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Table 2 Synthesis of pyrimido[4,5-b]carbazolone derivativesa
Entry
1
Substrate
Temp (°C)/time (h)
120/3
Product
Yieldb (%)
78
2
3a
3a
3a
3a
3a
120/3
120/3
120/3
120/3
120/6
120/5
120/3.5
120/3
120/6.5
77
72
74
69
57
71
73
75
51
3
4
5
6
7
8
9
10
a Reaction conditions: 3a–e (0.2 mmol), 4a–g (0.24 mmol), CuBr (0.01 mmol), K2CO3 (0.8 mmol) and DMSO (3.0 mL) under air. b Isolated yield.
recorded using tetramethylsilane (TMS) in the solvent of
DMSO-d6 as the internal standard (1H NMR: TMS at 0.00 ppm,
DMSO at 2.50 ppm; 13C NMR: DMSO at 39.5 ppm). Mass
spectra were recorded on either VG7070H mass spectrometer
using EI technique or Shimadzu-LCMS-2010A mass spec-
trometer. Elemental analyses (CHN) were recorded on a Thermo
Finnigan Flash EA 1112 analyzer in School of Chemistry, Uni-
versity of Hyderabad. IR spectra were recorded on Jasco FT/
IR-5300 spectrophotometer. Commercially available reagents
and solvents were used without further purification and were pur-
chased. Melting points were measured in open capillary tubes
and are uncorrected.
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3–7 h (see Table 2 in text for details). After completion of the
reaction, the resulting solution was cooled to room temperature,
poured into water and extracted with ethyl acetate. The solvent
of extract was removed with the aid of a rotary evaporator. The
residue was purified by column chromatography on silica gel
using ethyl acetate–hexanes as eluent to provide the desired
product 5a–j.
General procedure for synthesis of compounds (8a–b)
A Schlenk tube was charged with a magnetic pellet, evacuated
and back-filled with nitrogen. Substituted 2-bromo-9H-carba-
zole-3-carbonyl chloride 6a–b (0.28 mmol), pyridin-2-amine 7
(0.28 mmol), K2CO3 (0.85 mmol), and toluene (2.0 mL) were
added. After a 10 min stirring at room temperature under nitro-
gen atmosphere, charge Pd(OAc)2 (0.5 mol%) and CuI (5 mol
%). The mixture was stirred at 110 °C for 10 h under nitrogen
atmosphere. After completion of the reaction, the residue was
recrystallized from ethyl acetate–hexane (5 : 5) to afford the
desired product.
Scheme 2 Possible mechanism.
NOTE:
1
For the starting materials 3a–e, H NMR signals for amide
protons (CONH2) are not observed and for the compounds 5a–f
and 5i, the methyl (–CH3) protons merged with DMSO-d6 at δ
2.50 ppm.
Scheme 3 Synthesis of fused pyrimido[4,5-b]carbazolone derivatives.
Synthesis of 3a–e
2-Bromo-9-ethyl-6-methyl-9H-carbazole-3-carboxamide (3a)
A
mixture of 2-bromo-9-ethyl-6-methyl-9H-carbazole-3-car-
baldehyde 1a (1.0 g, 3.16 mmol) and THF (20 mL) was com-
bined in a 50 mL round bottom flask with magnetic stirring bar.
The mixture was cooled to 0 °C, followed by addition of 35%
H2O2 (5.23 mL, 52.3 mmol), KH2PO4 (0.45 g, 3.31 mmol) and
NaClO2 (0.56 g, 6.19 mmol) in water 10 mL was added drop-
wise. The reaction mixture was returned to room temperature and
stirred for 10 h. After completion of the reaction, acidified with
10% aq. HCl and filter the solid, recrystallized from warm ethyl
acetate to yield white solid (0.98 g, 93%).
The mixture of 2-bromo-9-ethyl-6-methyl-9H-carbazole-3-car-
boxylic acid 2a (1 g, 4.6 mmol), oxalyl chloride (2 mL) in
20 mL of dichloromethane and 2–3 drops of DMF was added at
0 °C and stirred for 12 h at room temperature. Oxalyl chloride
was removed by co-evaporation with toluene (10 mL) with
rotary evaporation. The concentrated crude product was dis-
solved in THF (20 mL). Ammonium hydroxide (5 mL, conc.)
was added drop wise to the mixture and stirred for 1 h at room
temperature. The precipitate was filtered and recrystallized from
ethyl acetate–hexanes (5 : 5) to afford the pure product 3a as
white solid (0.76 g, 77%). The remaining starting materials 3b–e
was also prepared using above described procedures.
Recrystallized from ethyl acetate–hexanes (5 : 5); Yield: 77%;
White solid; mp: 201–203 °C; IR (KBr): 3362, 2976, 1645,
1392, 1230, 1145, 682 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ
8.63 (s, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H),
7.30 (d, J = 8.4 Hz, 1H), 4.39 (q, J = 6.8 Hz, 2H), 2.44 (s, 3H),
1.25 (t, J = 6.8 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz): δ
167.9, 141.9, 139.1, 129.4, 128.5, 124.2, 122.5, 122.3, 121.3,
121.1, 118.9, 114.6, 109.9, 37.7, 21.4, 14.1; LC-MS: m/z = 332
[M], 334 [M + 2] positive mode; Anal. calcd for C16H15BrN2O:
C, 58.02; H, 4.56; N, 8.46%; Found: C, 58.12; H, 4.61; N,
8.56%.
2-Bromo-9-ethyl-9H-carbazole-3-carboxamide (3b)
Recrystallized from ethyl acetate–hexanes (5 : 5); Yield: 85%;
White solid; mp: 141–143 °C; IR (KBr): 3439, 2254, 1668,
1471, 1383, 1234, 1026, 821 cm−1 1H NMR (DMSO-d6,
;
400 MHz): δ 8.47 (s, 1H), 8.29 (d, J = 7.6 Hz, 2H), 8.24 (d, J =
8.0 Hz, 2H), 7.85 (s, 1H), 4.51 (q, J = 6.4 Hz, 2H), 1.33 (t, J =
6.8 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz): δ 162.8, 144.7,
140.4, 132.2, 129.2, 129.1, 128.9, 124.7, 123.9, 121.4, 119.8,
114.2, 111.3, 31.7, 13.8; LC-MS: m/z = 317 [M], 319 [M + 2]
positive mode; Anal. calcd for C15H13BrN2O: C, 56.80; H, 4.13;
N, 8.83%; Found: C, 56.75; H, 4.18; N, 8.91%.
General procedure for synthesis of pyrimido[5,4-b]carbazolone
derivatives (5a–j)
A 25 mL flask equipped with a magnetic stirring bar
was charged with substituted 2-bromo-carbazole-3-carboxamide
(0.2 mmol), (aryl)methanamine (0.24 mmol), K2CO3
(0.8 mmol) and CuBr (0.01 mmol) in DMSO (3.0 mL). The
mixture was allowed to stir under air (1 atm) at 120–130 °C for
9-Benzyl-2-bromo-9H-carbazole-3-carboxamide (3c)
Recrystallized from ethyl acetate–hexanes (5 : 5); Yield: 78%;
White solid; mp: 223–225 °C; IR (KBr): 3356, 1649, 1398,
1261, 1199, 1014, 696 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ
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1
8.41–8.40 (m, 1H), 8.38 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 8.00
(s, 1H), 7.96 (s, 1H), 7.67–7.64 (m, 2H), 7.53–7.47 (m, 2H),
7.29–7.22 (m, 1H), 7.13–7.10 (m, 1H), 5.72 (s, 2H); 13C NMR
(DMSO-d6, 100 MHz): δ 170.2, 141.2, 137.8, 130.5, 129.1,
127.8, 127.1, 127.04, 127.02, 122.2, 121.5, 121.2, 121.0, 120.3,
116.5, 113.9, 110.5, 46.1; LC-MS: m/z = 379 [M], 381 [M + 2]
positive mode; Anal. calcd for C20H15BrN2O: C, 63.34; H, 3.99;
N, 7.39%; Found: C, 63.25; H, 3.91; N, 7.45%.
1026, 763 cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.19 (s,
1H), 8.90 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 8.13 (s, 1H), 7.78 (s,
1H). 7.55 (d, J = 8.4 Hz, 1H), 7.37–7.35 (m, 1H), 7.16 (d, J =
8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H),
4.49 (q, J = 6.8 Hz, 2H), 3.86 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H);
13C NMR (DMSO-d6, 100 MHz): δ 163.3, 158.4, 150.8, 147.4,
144.6, 140.1, 133.2, 129.7, 129.2, 128.7, 125.6, 122.6, 121.4,
118.5, 114.4, 113.4, 109.5, 105.0, 55.9, 21.4, 13.8; LC-MS: m/z
= 384 [M + H]+, positive mode; Anal. calcd for C24H21N3O2: C,
75.18; H, 5.52; N, 10.96%; Found: C, 75.26; H, 5.48; N,
11.07%.
2-Bromo-9-butyl-6-methyl-9H-carbazole-3-carboxamide (3d)
Recrystallized from ethyl acetate–hexanes (5 : 5); Yield: 83%;
White solid, mp 197–198 °C; IR (KBr): 3377, 3177, 2957,
1
2864, 1645, 1481, 1211, 1105, 829 cm−1; H NMR (DMSO-d6,
10-Ethyl-7-methyl-2-p-tolyl-3H-pyrimido[4,5-b]carbazol-4(10H)-
one (5c)
400 MHz): δ 8.19 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.48 (d, J
= 6.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.35 (t, J = 7.2 Hz, 2H),
2.45 (s, 3H), 1.71–1.64 (m, 2H), 1.26–1.17 (m, 2H), 0.83 (t, J =
7.2 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz): δ 170.4, 141.2,
139.4, 129.6, 128.8, 128.3, 122.1, 120.9, 116.2, 113.6, 110.0,
42.6, 31.0, 21.4, 20.1, 14.1; LC-MS: m/z = 359 [M], 361
[M + 2] positive mode; Anal. calcd for C18H19BrN2O: C, 60.18;
H, 5.33; N, 7.80%; Found: C, 60.25; H, 5.39; N, 7.75%.
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 72%; Yellow solid;
mp 276–277 °C; IR (KBr): 3450, 2254, 2125, 1668, 1485, 1304,
1217, 1028, 760 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.22
(s, 1H), 8.91 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 7.79
(s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 4H), 4.49
(q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C
NMR (DMSO-d6, 100 MHz): δ 163.3, 151.2, 147.3, 144.6,
141.5, 140.2, 130.7, 129.6, 129.2, 128.7, 127.9, 122.8, 122.7,
121.4, 118.5, 113.5, 109.5, 105.2, 37.7, 21.5, 21.4, 13.8;
LC-MS: m/z = 368 [M + H]+, positive mode; Anal. calcd for
C24H21N3O: C, 78.45; H, 5.76; N, 11.44%; Found: C, 78.32; H,
5.71; N, 11.56%.
6-t-Butyl-2-bromo-9-ethyl-1,4-dimethyl-9H-carbazole-
3-carboxamide (3e)
Recrystallized from ethyl acetate–hexanes (2 : 8); Yield: 74%;
White solid; mp 109–110 °C; IR (KBr): 3437, 2961, 1649,
1454, 1365, 1236, 1168, 800 cm−1
;
1H NMR (CDCl3,
400 MHz): δ 8.21 (s, 1H), 7.62–7.60 (m, 1H), 7.40 (d, J = 8.8
Hz, 1H), 4.56 (q, J = 6.8 Hz, 2H), 2.94 (s, 3H), 2.91 (s, 3H),
1.47–1.44 (m, 12H); 13C NMR (CDCl3, 100 MHz): δ 174.0,
142.8, 139.8, 128.6, 127.8, 123.9, 123.1, 121.8, 119.0, 117.9,
108.6, 40.1, 34.7, 31.7, 19.1, 18.5, 15.5; LC-MS: m/z = 400
[M], 402 [M + 2] positive mode; Anal. calcd for C21H25BrN2O:
C, 62.85; H, 6.28; N, 6.98%; Found: C, 62.75; H, 6.32; N,
6.88%.
2-(4-Chlorophenyl)-10-ethyl-7-methyl-3H-pyrimido[4,5-b]-
carbazol-4(10H)-one (5d)
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 74%; Pale yellow
solid; mp 284–285 °C; IR (KBr): 3381, 2968, 2922, 1637, 1593,
1483, 1342, 1234, 1089, 794 cm−1 1H NMR (DMSO-d6,
;
400 MHz): δ 12.38 (s, 1H), 8.93 (s, 1H), 8.25 (d, J = 8.4 Hz,
2H), 8.15 (s, 1H), 7.83 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.56
(d, J = 8.4 Hz, 1H), 7.39–7.37 (m, 1H), 4.50 (q, J = 7.2 Hz,
2H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz):
δ 163.2, 150.3, 147.0, 144.5, 140.2, 136.4, 132.3, 129.9, 129.3,
129.1, 128.9, 123.0, 122.6, 121.5, 118.6, 113.6, 109.6, 105.4,
37.7, 21.4, 13.8; LC-MS: m/z = 387 [M], 388 [M + 1] positive
mode; Anal. calcd for C23H18ClN3O: C, 71.22; H, 4.68; N,
10.83%; Found: C, 71.35; H, 4.62; N, 10.76%.
10-Ethyl-7-methyl-2-phenyl-3H-pyrimido[4,5-b]carbazol-
4(10H)-one (5a)
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 78%; Pale yellow
solid; mp >300 °C; IR (KBr): 3391, 2253, 2125, 1651, 1377,
1145, 1026, 763 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.30
(s, 1H), 8.93 (s, 1H), 8.26–8.24 (m, 2H), 8.15 (s, 1H), 7.83 (s,
1H), 7.58–7.55 (m, 4H), 7.38 (d, J = 8.4 Hz, 1H), 4.50 (q, J =
7.2 Hz, 2H), 1.34 (t, J = 6.8 Hz, 3H); 13C NMR (DMSO-d6,
100 MHz): δ 163.2, 151.2, 147.2, 144.6, 140.2, 133.5, 131.5,
129.2, 129.0, 128.8, 128.0, 122.9, 122.7, 121.5, 118.6, 113.6,
109.5, 105.3, 37.7, 21.4, 13.8; LC-MS: m/z = 354 [M + H]+,
positive mode; Anal. calcd for C23H19N3O: C, 78.16; H, 5.42;
N, 11.89%; Found: C, 78.35; H, 5.48; N, 11.79%.
10-Ethyl-2-(4-fluorophenyl)-7-methyl-3H-pyrimido[4,5-b]-
carbazol-4(10H)-one (5e)
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 69%; Pale yellow
solid; mp 291–292 °C; IR (KBr): 3414, 2962, 2856, 2258, 1649,
1481, 1304, 1240, 1024, 825 cm−1 1H NMR (DMSO-d6,
;
400 MHz): δ 12.33 (s, 1H), 8.91 (s, 1H), 8.31–8.28 (m, 1H),
8.13 (s, 1H), 7.80 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.43–7.36
(m, 4H), 4.49 (q, J = 6.8 Hz, 2H), 1.34 (t, J = 6.8 Hz, 3H); 13C
NMR (DMSO-d6, 100 MHz): δ 163.2, 150.3, 147.1, 144.6,
140.2, 130.6, 130.5, 130.0, 129.3, 128.8, 123.0, 122.7, 121.4,
118.5, 116.1, 115.9, 113.5, 109.8, 109.5, 105.3, 37.7, 21.4, 13.8;
LC-MS: m/z = 372 [M + H]+, positive mode; Anal. calcd for
10-Ethyl-2-(4-methoxyphenyl)-7-methyl-3H-pyrimido[4,5-b]-
carbazol-4(10H)-one (5b)
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 77%; Yellow solid;
mp 198–199 °C; IR (KBr): 3441, 2253, 2125, 1651, 1377, 1145,
This journal is © The Royal Society of Chemistry 2012
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C23H18FN3O: C, 74.38; H, 4.88; N, 11.31%; Found: C, 74.21;
H, 4.82; N, 11.25%.
(m, 2H), 1.34–1.28 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR
(DMSO-d6, 100 MHz): δ 162.8, 147.0, 146.9, 145.0, 140.6,
138.3, 132.1, 129.3, 129.2, 128.9, 128.7, 122.6, 122.5, 121.3,
118.7, 113.4, 109.7, 105.0, 42.8, 30.9, 21.4, 20.2, 14.2; LC-MS:
m/z = 388 [M + H]+, positive mode; Anal. calcd for
C23H21N3SO: C, 71.29; H, 5.46; N, 10.84%; Found, C, 71.35;
H, 5.41; N, 10.96%.
10-Ethyl-2-(furan-2-yl)-7-methyl-3H-pyrimido[4,5-b]carbazol-
4(10H)-one (5f)
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 57%; Yellow solid;
mp 248–250 °C. IR (KBr): 3462, 2254, 2127, 1653, 1026,
1
823 cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.25 (s, 1H),
7-t-Butyl-10-ethyl-5,11-dimethyl-2-(thiophen-2-yl)-3H-pyrimido-
[4,5-b]carbazol-4(10H)-one (5j)
8.89 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.61 (m,
1H), 7.54 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H),
6.76–6.75 (m, 1H), 4.48 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz,
3H); 13C NMR (DMSO-d6, 100 MHz): δ 162.6, 147.0, 146.9,
146.7, 144.5, 143.2, 140.1, 129.2, 129.8, 122.8, 122.7, 121.4,
118.7, 114.2, 113.7, 112.9, 109.5, 105.2, 37.7, 21.4, 13.8;
LC-MS: m/z = 344 [M + H]+, positive mode; Anal. calcd for
C21H17N3O2: C, 73.45; H, 4.99; N, 12.24%; Found: C, 73.36;
H, 4.92; N, 12.15%.
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 51%; Yellow solid;
mp 173–174 °C; IR (KBr): 3429, 2254, 2129, 1660, 1028,
1
825 cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.20 (s, 1H),
8.28 (s, 1H), 8.21–8.20 (m, 1H), 7.83–7.82 (m, 1H), 7.62–7.61
(m, 2H), 7.24–7.22 (m, 1H), 4.70 (q, J = 6.4 Hz, 2H), 3.45 (s,
3H), 3.08 (s, 3H), 1.43 (s, 12H); 13C NMR (DMSO-d6,
100 MHz): δ 164.3, 146.0, 145.2, 142.8, 140.9, 138.7, 134.4,
131.8, 128.99, 128.91, 124.5, 23.3, 122.6, 119.7, 114.9, 113.0,
112.2, 109.3, 34.8, 32.2, 18.5, 15.7, 14.4; LC-MS: m/z = 428
(M − H)+, negative mode; Anal. calcd for C26H27N3OS: C,
72.69; H, 6.34; N, 9.78%; Found: C, 72.56; H, 6.31; N, 9.65%.
2-(4-Chlorophenyl)-10-ethyl-3H-pyrimido[4,5-b]carbazol-
4(10H)-one (5g)
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 71%; Pale yellow
solid; mp 286–288 °C; IR (KBr): 3427, 2254, 2129, 1668, 1026,
12-Ethyl-9-methylpyrido[2′,1:2,3]pyrimido[4,5-b]carbazol-
6(12H)-one (8a)
9 99 825 cm−1 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (s,
;
1H), 9.04 (s, 1H), 8.47 (s, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.24
(d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.54
(d, J = 8.4 Hz, 2H), 4.51 (q, J = 6.4 Hz, 2H), 1.34 (t, J = 6.0 Hz,
3H); 13C NMR (DMSO-d6, 100 MHz): δ 162.8, 147.5, 144.7,
140.4, 132.2, 130.0, 129.9, 129.2, 129.1, 128.9, 124.7, 123.9,
121.4, 119.8, 114.2, 111.3, 105.8, 31.7, 13.8; LC-MS: m/z = 373
[M]+, 374 [M + 1] positive mode; Anal. calcd for C22H16ClN3O:
C, 70.68; H, 4.31; N, 11.24%; Found: C, 70.59; H, 4.36; N,
11.28%.
Recrystallized from ethyl acetate–hexanes (2 : 8); Yield: 70%;
Bright yellow solid; mp 269–270 °C; IR (KBr): 3096, 3018,
2966, 1672, 1527, 1423, 1304, 1234, 1124, 829 cm−1; 1H NMR
(CDCl3, 400 MHz): δ 9.15 (s, 1H), 8.93–8.91 (m, 1H), 8.02 (s,
1H), 7.61 (s, 1H), 7.48–7.47 (m, 2H), 7.38–7.30 (m, 2H),
6.82–6.81 (m, 1H), 4.39 (q, J = 7.6 Hz, 2H), 2.57 (s, 3H), 1.49
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.5,
147.0, 146.6, 145.6, 140.3, 133.6, 129.6, 128.4, 126.8, 125.7,
123.6, 123.0, 121.2, 119.6, 111.3, 109.3, 108.2, 102.0, 38.0,
21.3, 13.3; LC-MS: m/z = 328 (M + H)+, positive mode; Anal.
calcd for C21H17N3O: C, 77.04; H, 5.23; N, 12.84%; Found: C,
77.15; H, 5.19; N, 12.75%.
10-Benzyl-2-phenyl-3H-pyrimido[4,5-b]carbazol-4(10H)-one (5h)
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 73%; Yellow solid;
mp >300 °C; IR (KBr): 3499, 2253, 2127, 1651, 1028, 823,
12-Benzylpyrido[2′,1′:2,3]pyrimido[4,5-b]carbazol-6(12H)-one (8b)
1
756 cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.37 (s, 1H),
9.04 (s, 1H), 8.41 (d, J = 7.6 Hz, 1H), 8.23–8.20 (m, 1H), 7.88
(s, 1H), 7.71 (d, J = 8 Hz, 1H), 7.58–7.54 (m, 4H), 7.31–7.23
(m, 6H), 5.79 (s, 2H); 13C NMR (DMSO-d6, 100 MHz): δ
163.2, 151.5, 147.4, 145.0, 142.6, 137.8, 133.4, 131.6, 129.1,
129.0, 128.0, 127.8, 127.7, 127.2, 123.1, 122.6, 121.7, 120.6,
118.9, 114.2, 110.2, 106.0, 46.3; LC-MS: m/z = 402 [M + H]+,
positive mode; Anal. calcd for C27H19N3O: C, 80.78; H, 4.77;
N, 10.47%; Found: C, 80.65; H, 4.85; N, 10.36%.
Recrystallized from ethyl acetate–hexanes (3 : 7); Yield: 58%;
Pale yellow solid; mp 283–284 °C; IR (KBr): 2924, 1635, 1531,
1431, 1253, 1084, 1018, 802 cm−1
;
1H NMR (CDCl3,
400 MHz): δ 8.41–8.40 (m, 1H), 8.38 (s, 1H), 8.26 (d, J = 6.0
Hz, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.67–7.64 (m, 4H),
7.53–7.47 (m, 4H), 7.29–7.22 (m, 1H), 7.13–7.10 (m, 1H), 5.72
(s, 2H); 13C NMR (CDCl3, 100 MHz): δ 170.4, 148.4, 141.1,
138.6, 136.2, 129.9, 127.7, 126.9, 126.6, 126.2, 122.4, 122.3,
120.7, 120.6, 120.1, 119.7, 119.4, 115.8, 114.1, 112.8, 112.3,
109.3, 108.8, 46.7; LC-MS: m/z = 376 (M + H)+, positive mode;
Anal. calcd for C25H17N3O: C, 79.98; H, 4.56; N, 11.19%;
Found: C, 79.83; H, 4.61; N, 11.09%.
10-Butyl-7-methyl-2-(thiophen-2-yl)-3H-pyrimido[4,5-b]-
carbazol-4(10H)-one (5i)
Eluent: ethyl acetate–hexanes (7 : 3); Yield: 75%; Yellow solid;
mp 268–270 °C; IR (KBr): 3437, 2934, 2150, 1666, 1496, 1439,
1390, 1255, 1101, 661 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ
12.41 (s, 1H), 8.87 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.84 (d, J
= 5.2 Hz, 1H), 7.70 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.34 (d, J
= 7.6 Hz, 1H), 7.23 (s, 1H), 4.43 (t, J = 6.8 Hz, 2H), 1.76–1.73
Acknowledgements
We gratefully acknowledge DST for financial assistance (Project
number: SR/S1/OC-70/2008). DKS and NR also thank CSIR for
SRF & JRF fellowship.
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