One-pot multi-component synthesis of pyrimido[4,5-b]indoles in solvent-free condition

Article abstract of DOI:10.1007/s13738-013-0366-6

Pyrimido[4,5-b]indole derivatives 4 were synthesized from a one-pot three-component reaction of aryl aldehyde 1, oxindole 2 and urea/thiourea 3 in solvent-free condition using ytterbium(III) triflate as catalyst.

Full text of DOI:10.1007/s13738-013-0366-6

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0366-6
ORIGINAL PAPER
One-pot multi-component synthesis of pyrimido[4,5-b]indoles
in solvent-free condition
•
Swarup Majumder Pulak J. Bhuyan
Received: 1 August 2013 / Accepted: 2 October 2013
Ó Iranian Chemical Society 2013
Abstract Pyrimido[4,5-b]indole derivatives 4 were syn-
thesized from a one-pot three-component reaction of aryl
aldehyde 1, oxindole 2 and urea/thiourea 3 in solvent-free
condition using ytterbium(III) triflate as catalyst.
neuropeptide Y receptor ligands [10] and potential tyrosine
kinases inhibitors [11]. Pyrimidoindole is a class of ann-
elated pyrimidines which has got tremendous attention of
the scientists due to their biological activities, and
numerous reports are present for the synthesis of these
compounds. Zhang et al. [12] have reported the synthesis
Keywords Pyrimido[4,5-b]indoles Á Multi-
component reactions (MCRs) Á Ytterbium(III) triflate Á
Solvent-free reaction
of pyrimido[4,5-b]indoles via
a palladium-catalyzed
intramolecular arylation of pyrimidine substrates. Mizar
and Myrboh [13] have also reported the synthesis of fused
pyrimidines using KF–alumina as catalyst in ethanol. But
most of the reactions have suffered from one or more
disadvantages like toxic organic solvent, expensive cata-
lyst, ligand or additives, requirement inert atmosphere.
Therefore, there is still the requirement for the efficient
method for the synthesis of pyrimidoindole derivatives
particularly in terms of operational simplicity, reusability,
and economic viability.
Introduction
Multi-component reactions [1–6], with various advantages
such as convergence, low energy consumption, minimum
waste production, facile execution, high selectivity, and
high yield of products etc., represent an important platform
for the design and discovery of various drugs and drug-
related molecules.
Solvent-free reaction and transfer of solution phase to
solid phase have rapidly become an area of intense research
activity and key technology for pharmaceutical research.
This avoids problems associated with the use of excess
chemicals and the waste disposal of harmful solvents [14].
The Lewis acid catalysts are of great significance in
organic chemistry, which initiate carbon–carbon bond
formation with unique activity and selectivity under mild
reaction conditions. In this regard, lanthanide salt-mediated
reaction have got special attention due to their low toxicity,
low cost, ease of handling, stability, and recoverability of
the reagent from water [15].
Depending on the position of nitrogen atom, three iso-
meric structures of diazines are possible. These are pyrid-
azine 1, pyrimidine 2 and pyrazine 3 (Fig. 1). When
pyrimidine ring contains keto or enol group in the ring, it is
called as pyrimidinone. Compounds with pyrimidinone
scaffolds obtained from both nature and synthetic origin
possess diverse biological activities such as anti-hyper-
tensive and anti-inflammatory activities [7]. They also act
as A1 adenosine receptor antagonists [8, 9], CFR1 and
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0366-6) contains supplementary
material, which is available to authorized users.
Experimental section
S. Majumder (&) Á P. J. Bhuyan
Medicinal Chemistry Division, CSIR-North East Institute of
Science and Technology, Jorhat 785006, Assam, India
e-mail: majumderswar@yahoo.co.in
All chemicals were purchased from Merck and Aldrich
chemical companies. All reagents and solvents were used
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J IRAN CHEM SOC
6.85–6.92 (m, 2H), 7.19–7.84 (m, 7H), 8.60 (s, br, 1H),
11.25 (s, br, 1H); 13C NMR (75 MHz, DMSO-d6) d 110.31,
121.70, 121.85, 123.04, 127.65, 128.33 (2C), 128.69,
129.71, 130.58, 131.99, 134.83, 137.60, 139.69, 148.66,
170.51. MS (EI) 262.4 (M?H)?.
N
N
N
N
N
N
Pyrimidines
Pyridazine
Pyrazine
3
2
1
Compound 4n: light yellow solid: 0.332 g (60 %),
m.p. [ 300 °C. IR (KBr) mmax = 3,442, 3,098.
N
O
N
1
1,420 cm-1. H NMR (300 MHz, DMSO-d6): d 6.95–7.89
OH
N
N
H
(m, 9H). 11.57 (s, br, 1H). 13C NMR (75 MHz, DMSO-d6):
d 110.47, 121.68, 121.83, 123.01, 127.78, 128.68 (2C),
129.37 (2C), 129.70 (2C), 129.95, 134.86, 147.58, 156.87,
179.84. MS (EI) 278.2 (M?H)?.
Pyrimidinone
Fig. 1 Biological active diazines
without drying. All IR spectra were recorded on Perkin
Elmer system 2000 FTIR spectrometer. 1HNMR and
13CNMR spectra were recorded on Bruker Avance-DPX
300 and 75 MHz FTNMR in DMSO-d6 solvent using TMS
as an internal standard. Chemical shifts were reported in
ppm (d units). Mass spectra were recorded in Bruker
Daltonics ESQUIRE 3000 LC ESI ion trap mass spec-
trometer. Analytical thin layer chromatography was per-
formed using E-Merck aluminium-backed silica gel plates
coated with 0.2-mm-thick silica gel. Melting points
(uncorrected) were determined in open capillary tubes on a
Buchi B-540 apparatus.
Results and discussion
As part of our continued interest on indole derivatives and
synthesis of diverse heterocyclic compounds of biological
significance [16–19], recently we have reported an efficient
method for the synthesis of a-carbolines from a one-pot
three-component reaction [20]. In the present paper, we
describe the synthesis of some novel pyrimido[4,5-b]indole
derivatives 4 from a one-pot three-component reaction of
aryl aldehyde 1, oxindole 2 and urea/thiourea 3 in solvent-
free condition using ytterbium triflate as a catalyst
(Scheme 1).
Initially, a mixture containing aldehyde 1 (2 mmol),
oxindole 2 (2 mmol) and urea or thiourea 3 (2.5 mmol)
was investigated in the absence of any catalyst (Table 1,
entry-1), no product was formed instead it afforded a black
General procedure for the synthesis of 4
A mixture of aldehyde 1 (2 mmol), oxindole 2 (2 mmol),
urea/thiourea
3
(2.5 mmol) and ytterbium triflate
(10 mol%) was heated with stirring at 100 °C for 1–3 h.
After cooling, the reaction mixture was poured into crushed
ice with stirring. The crude product was filtered, washed
with cold water, dried, and recrystallized from 95 % eth-
anol or ethyl acetate. The pure product 4 was obtained in
52–72 % yield. After isolation of the product, the aqueous
layer was extracted by ethylacetate (10 9 3 ml). Yb(OTf)3
can be recovered by removing the water and can then be
reused after recrystallization from CH3CN/CH2Cl2.
Ar
X
NH
Yb(OTf)3
ArCHO
H2N
NH2
100oC, neat
1h
X
O
N
R
N
N
R
2
3
1
4
X = O, S
R= H, CH3, COCH3
Scheme 1 Synthesis of pyrimido[4,5-b]indoles
Table 1 Catalyst screening for pyrimido[4,5-b] indole derivatives
Yield (%)a
Spectral data of selected compound (4a)
Entry
Catalyst (10 mol%)
Temp. (°C)
1.
2.
3.
4.
5.
6.
7.
8.
Neat
Fused
100
100
100
100
100
100
100
NR
60
25
65
55
75
60
62
Compound 4a: yellow solid: 0.393 g (65 %),
m.p. [ 300 °C. IR (KBr) mmax = 3,441, 3,084, 1,735,
InCl3
1
1,644 cm-1. H NMR (300 MHz, DMSO-d6): d 2.65 (s,
TsOH
CH3COOH
L-proline
3H), 6.90–7.04 (m, 2H), 7.23–7.79 (m, 7H), 11.62 (s, br,
1H); 13C NMR (75 MHz, DMSO-d6) d 14.6, 110.40,
121.33, 121.76, 123.56, 127.85, 128.61, 128.59 (2C),
129.58, 130.18, 131.82, 133.57, 134.74, 137.79, 141.69,
159.45, 170.24. MS (EI) 304.5 (M?H)?.
Yb(OTf)3
Yb(OTf)3 (20 mol%)
Yb(OTf)3 (30 mol%)
Compound 4 h: white solid: 0.328 g (63 %),
m.p. [ 300 °C. IR (KBr) mmax = 3,439, 3,195, 3,025,
Reaction conditions: oxindole 1 (1 mmol), aldehyde 2 (1 mmol) and
urea (1.5 mmol) were heated for 1 h in the absence of any solvent
a
1,734, 1,618 cm-1 1H NMR (300 MHz, DMSO-d6): d
.
Isolated yield
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J IRAN CHEM SOC
precipitate due to excessive heating. When the reaction was
conducted in the presence of catalytic amount of ytterbium
triflate [Yb(OTf)3], a satisfying result was obtained. Use of
10 mol% of Yb(OTf)3 (Table 1, entry-6), at 100 °C under
optimized reaction conditions, was found to be sufficient
for optimum yields of the desired products and an increase
in the amount of catalyst (Table 1, entries 7, 8) did not
improve the yields of the product. Encouraged by the yield
of product, we extended the reaction using different cata-
lysts (Table 1, entries 2–5), but no satisfactorily results
were obtained except for Yb(OTf)3.
Table 2 Yb(OTf)3-catalyzed one-pot synthesis pyrimido[4,5-b]
indole derivatives 4
Ar
NH
X
Yb(OTf)3
X
ArCHO
N
H2N
NH2
O
1-3 h
N
R
N
R
1a-f
2a-b
4a-o
3a-b
Entry
Ar
R
X
Time
(min)
Product
Yield
(%)
1.
Ph
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
H
O
O
O
O
O
O
O
O
O
O
O
O
O
S
90
100
120
45
4a
4b
4c
4d
4e
4f
65
56
53
69
72
70
58
63
52
49
67
69
50
60
55
61
65
2.
p-CH3
In the next step, the substrate scope of the reaction was
investigated using aldehyde, urea/thiourea, and substituted
oxindole. All the reactions, consisting of those involving
ortho- and para-substituted benzaldehydes, proceeded
smoothly, and afforded the corresponding pyrimido[4,5-
b]indoles in moderate to high yields. Electronic effects
could be observed in the reaction process. The electron-
donating group (EDG) at the para position of the benz-
aldehydes required prolonged reaction time to give com-
paratively less yields of the product (Table 2, entries 2, 3,
8–10 and 14–16), while stronger EWG-substituted ones
gave evidently high yields (Table 2, entries 4–6, 11 and
17). Ortho-substituted benzaldehydes, irrespective of
EDG or EWG, afforded the corresponding pyrimidinones
in relatively lower yields, indicating an obvious steric
effect (Table 2, entry 7 and 13). The use of thiourea
instead of urea afforded corresponding pyrimidinones-
2(1H)-thiones in comparable yields (Table 2, entries
15–17).
3.
p-CH3OPh
p-BrPh
p-ClPh
p-NO2Ph
p-OHPh
Ph
4.
5.
50
6.
80
7.
120
100
110
130
60
4g
4h
4i
8.
9.
p-CH3Ph
p-CH3OPh
p-BrPh
p-NO2Ph
o-OHPh
Ph
H
10.
11.
12.
13.
14.
15.
16.
17.
H
4j
H
4k
41
4m
4n
4o
4p
4q
H
125
140
110
120
130
85
H
H
p-CH3Ph
Ph
H
S
CH3
CH3
S
p-BrPh
S
peak at 304.5 (M?H)?. A variety of aldehydes 1a–f,
oxindole 2a, b, and urea/thiourea 3a, b were made to react
under these reaction conditions to afford the corresponding
pyrimido[4,5-b]indole derivatives 4a–o. The results
obtained are presented in Table 2.
On further optimization, the influence of temperature
was examined for the model reaction. Raising the reaction
temperature from 60 to 90 °C led to an increase in yield,
while the temperature over 100 °C resulted in decreased
yield. Then the effect of reaction time on yield was
investigated and the highest yield was obtained after 1 h.
The results showed that lower temperature and shorter
reaction time may result in incomplete reaction, while
overheating and excessively prolonged time lead to com-
plicated side reactions. We first examined the reaction in
different solvents including acetonitrile, ethanol, dioxane,
toluene, and in solvent-free conditions at 100 °C. The best
results were obtained under solvent-free conditions.
After completion of reaction in optimized condition, the
mixture was cooled at room temperature and then poured
into water. The solid product that appeared was filtered and
recrystallized. The structure of the compound was ascer-
A probable mechanism is outlined in Scheme 2. The
first step of the mechanism is probably a Lewis acid-
catalyzed cross-aldol condensation of aldehyde with
oxindole to produce A, which is similar to the Yb(OTf)3-
catalyzed reaction described by Wang et al. [21]. Then
the Michael addition of urea to A leads to ureide B,
which subsequently cyclizes by eliminating water and
then undergoes aerial oxidation to form pyrimidinone
derivatives (Scheme 2).
In conclusion, we describe in this study an efficient
method for the synthesis of pyrimido[4,5-b]indoles by
Yb(OTf)3-catalyzed one-pot three-component reaction of
aromatic aldehyde, oxindole, and urea/thiourea under sol-
vent-free conditions. Several advantages of the reaction are
that they are clean, one-pot, and can be handled easily. The
catalyst can be easily recovered from the aqueous layer
after the completion of the reaction and reused with no loss
of activity. These environmentally friendly features make
1
tained as 4a from the spectroscopic data. The H NMR
spectrum showed the presence of nine protons in aromatic
zone and a single broad peak at d 11.62 indicates the
presence of NH proton. The IR spectrum showed the peak
at 3,441 and 3,084 cm-1, thus clearly indicating the pre-
sence of NH proton. The mass spectrum revealed a strong
123

J IRAN CHEM SOC
[Yb]
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[Yb]
H
H
H
O
O
O
O
O
Yb(OTf)3
HC
CH
Ar
O
O
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Ar
RN
RN
N
R
Ar
H
[Yb]
Ar
Ar
Ar
NH
_
RN
H2O
H2N
X
CO(NH2)2
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N
OH
H
H2N
N
N
O
H
R
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A
[Yb]
Ar
B
Ar
H
H
Ar
H
NH
_
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H2O
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X
X
X
N
H
N
N
N
N
O
H
N
R
H
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H
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OH
[Yb]
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Aerial oxidation
Ar
NH
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Scheme 2 Possible mechanism of pyrimido[4,5-b]indole derivatives
4
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the catalytic procedure a practically and environmentally
acceptable method for the synthesis of pyrimido[4,5-
b]indole derivatives.
Acknowledgments The authors thank DST and CSIR, New Delhi,
for financial support (CAAF-NE project). SM thanks CSIR, New
Delhi for the award of Senior Research Fellowship.
123