Synthesis of pyrido[2,3-b]indoles and pyrimidoindoles via Pd-catalyzed amidation and cyclization

Article abstract of DOI:10.1039/c2ob25371b

Biologically and pharmaceutically active core structures containing a new class of 4-hydroxy-α-carbolines, dihydropyrido[2,3-b]indoles, pyrimido[4,5-b] and [5,4-b]indoles have been synthesized in good yields via Pd-catalyzed amidation and cyclizations. The keto-enol tautomerism in 4-hydroxy-α-carbolines has been investigated by DFT calculations and spectroscopic techniques. The fluorescence studies of pyrimido[4,5-b] and [5,4-b]indoles were carried out with good quantum yields.

Full text of DOI:10.1039/c2ob25371b

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PAPER
Synthesis of pyrido[2,3-b]indoles and pyrimidoindoles via Pd-catalyzed
amidation and cyclization†
Arepalli Sateesh Kumar, P. V. Amulya Rao and Rajagopal Nagarajan*
Received 21st February 2012, Accepted 24th April 2012
DOI: 10.1039/c2ob25371b
Biologically and pharmaceutically active core structures containing a new class of
4-hydroxy-α-carbolines, dihydropyrido[2,3-b]indoles, pyrimido[4,5-b] and [5,4-b]indoles have been
synthesized in good yields via Pd-catalyzed amidation and cyclizations. The keto–enol tautomerism in
4-hydroxy-α-carbolines has been investigated by DFT calculations and spectroscopic techniques.
The fluorescence studies of pyrimido[4,5-b] and [5,4-b]indoles were carried out with good quantum
yields.
Introduction
Among the myriad of biologically active heterocycles, nitrogen
containing heterocycles1 play a key role. In fact, recent surveys
have reported that a large number of molecules currently under
investigation by researchers contain nitrogen heterocycles, and
of these, pyrido[2,3-b]indoles, pyrimido[4,5-b] and [5,4-b]-
indoles constitute the most important family of compounds.
These heterocycles have the common “privileged” indole frame-
work which is commonly found in pharmaceutical drugs and
natural products.2 Therefore, there has been substantial interest
in developing efficient methods for the synthesis of these core
structures.
Pyrido[2,3-b]indoles (α-carbolines) are considered compounds
of great interest for their wide range of biological activities, such
as antitumor,3 antiviral,4 anti-inflammatory,5 and anxiolytic, and
are also useful for the treatment of cancer and immune-related
diseases.6a These novel biological activities are due to their
ability to interact with DNA, which depends on the planarity of
the pyrido[2,3-b]indole ring system and its functional groups.
The core structure of pyrido[2,3-b]indole is present in naturally
occurring alkaloids (Fig. 1), such as grossularines 1 and 2,
dendrodoine A (isolated from Dendrodoa grossularia),3 and
mescengricin (isolated from Streptomyces griseoflavu),6b, carci-
Fig. 1 Biologically and pharmaceutically active pyrido[2,3-b]indoles,
pyrimido[4,5-b] and [5,4-b]indoles.
nogenic metabolites and the pyrolysis products from protein
foods.7a,b In general, the construction of these pyrido[2,3-b]-
indole core sturctures can be achieved by one of the following
processes: (a) cyclization of azaindoles,7c,d or (b) annulation of
pyridine rings.7e
Pyrimido[4,5-b] and [5,4-b]indole moieties8 are also promi-
nent structural motifs discerned in numerous pharmaceutically
active compounds and show a wide range of significant bio-
logical activities, (Fig. 1) such as anti-asthma,9 antihypertensive
and anti-inflammatory,10 and act as α1-adrenergic receptor
ligands or A1 adenosine receptor antagonists,11 potential tyrosine
kinases (PTK) inhibitors, CFR1 and neuropeptide Y receptor
ligands.12a Pyrimido[4,5-b] and [5,4-b]indoles are also called
3-aza-α-carbolines and 2-aza-β-carbolines respectively.12b,c
School of Chemistry, University of Hyderabad, Hyderabad – 500046,
India. E-mail: rnsc@uohyd.ernet.in; Fax: +91 40 23012460
†Electronic supplementary information (ESI) available: Spectra and
analytical data of all compounds. See DOI: 10.1039/c2ob25371b
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yielding the corresponding pyrido[2,3-b]indol-4(9H)-ones.
Results and discussion
1
But interestingly, the H and 13C NMR data points towards the
Due to the ubiquity of these molecular core structures in many
biologically and pharmaceutically important molecules, we are
exploring the synthetic methods to construct pyrido[2,3-b]-
indoles, pyrimido[4,5-b] and [5,4-b]indoles through the Pd-cata-
lyzed amidation reactions of 2-formyl-3-haloindoles and 2-halo-
3-carbonylindoles followed by cyclizations. Over the past
decade, Pd-catalyzed cross-coupling reactions have emerged as a
crucial tool in organic synthesis. Among them, Pd-catalyzed
C–N bond formation reactions have great uses in organic syn-
thesis and pharmaceuticals. These reactions, pioneered by the
groups of Buchwald and Hartwig,13 have been extensively
studied. On account of an interest in the synthesis of indole
fused heterocycles,14 we first performed amidation at both the
3rd and 2nd positions of 2-formyl-3-haloindoles and 2-halo-3-
carbonylindoles.
To obtain the best reaction conditions, we probed the con-
ditions under which the coupling of 1-benzyl-3-chloro-1H-
indole-2-carbaldehyde, thiophene-2-carboxamide and 3-bromo-
1-ethyl-1H-indole-2-carbaldehyde with benzamide, for amida-
tion at the 3rd position, proceeded smoothly. We also probed the
reaction conditions under which the coupling of 2-bromo-1-
ethyl-1H-indole-3-carbaldehyde with thiophene-2-carboxamide,
for amidation at the 2nd position, proceeded smoothly. We
screened various Pd sources, ligands and solvents as shown in
Tables S1A and S1B (ESI†).18 We found that the best reaction
conditions for the amidation at the 3rd position of 2-formyl-3-
haloindoles involves 1.0 equiv. of 2-formyl-3-chloroindoles or
2-formyl-3-bromoindoles, 1.2 equiv. of amide, 0.75 mol%
Pd2(dba)3, 0.50 mol% BINAP, and 3.0 equiv. of Cs2CO3. For the
amidation at the 2nd position of 2-halo-3-haloindoles, the best
reaction conditions involve 1.0 equiv. of 2-formyl-3-chloro-
indoles or 2- formyl-3-bromoindoles, 1.2 equiv. of amide,
0.75 mol% Pd2(dba)3, 0.50 mol% BINAP and 3.0 equiv. of
Cs2CO3, and for the amidation at the 2nd position of 2-halo-3-
carbonylindoles, best conditions involve 0.50 mol% Pd2(dba)3,
0.25 mol% BINAP, 3.0 equiv. of Cs2CO3 and 2.0 mL mmol−1 of
t-BuOH as solvent for the substrates 2-formyl-3-chloroindoles
and 2-chloro-3-carbonylindoles whereas toluene is the suitable
solvent for 2-formyl-3-bromoindoles and 2-bromo-3-carbonyl-
indoles at 110 °C. By applying these conditions we synthesized
various new N-(3-carbonyl-1-(substituted)-1H-indol-2-yl)amides
(1f–u) and N-(1-(substituted)-2-formyl-1H-indol-3-yl)amides
(1a–e) in good to excellent yields as shown in Table 1. These
amide derivatives offer access to various indole fused hetero-
cyclic ring systems. Having established a successful method for
the synthesis of various new N-(3-acetyl-1-(substituted)-1H-
indol-2-yl)amides, we proceeded to the base catalyzed Camps15
cyclization of these amides to yield 2-substituted-pyrido[2,3-b]-
indol-4(9H)-ones.
formation of 4-hydroxy-α-carbolines rather than the expected
pyrido[2,3-b]indol-4(9H)-ones as the products. We anticipated
that the product may be involved in keto–enol tautomerism
which was investigated by carrying out various theoretical and
spectroscopic studies.
Generally, aliphatic carbonyl compounds which have α-hydro-
gens undergo keto–enol tautomerism; the keto form is favoured
over the enol form due to the stabilization of the carbonyl bond.
This general rule is not obeyed by the cyclic conjugated ketone
systems; the enol form is predominant over the keto form and
the existence of the enol form is supported by the literature16.
We have proved the existence of enol form by performing spec-
troscopic studies and electronic structure calculations on the
isomers of these molecules.
A density functional theory (DFT) hybrid method with the
Becke’s 3 parameter exchange functional basis set of Lee, Yang
and Parr [(B3LYP) and 6-31+G(D) (valence double zeta plus
polarization functions of d type)] was used to optimize the geo-
metries of the two tautomers of the 9-ethyl-2-methyl-1H-pyrido-
[2,3-b]indol-4(9H)-one (2a). The effect of solvation was also
studied here. Three types (gas phase, using MeOH and THF as
solvents with polarizable continuum model (PCM) solvent
model) of calculations were done on the two tautomers. All the
calculations were done using Gaussian 09 package. It is well
recognized that this method and basis set are reliable for organic
molecules. The two structures converged to a minimum and both
minima were verified by establishing that the matrix of energy
second derivatives (Hessian) has only positive Eigen values (all
vibrational frequencies real). The optimized keto and enol forms
are depicted by Fig. S2a and S2b (ESI†).18 The transition state is
verified by the presence of only one large negative vibrational
frequency at −1671 cm−1. The obtained transition state is
depicted in Fig. S2c.†18
The electronic and activation energies of the two tautomers
and transition states in the three models of theory are tabulated
in Table 3. From Table 3, it can be seen that the relative energy
difference between the enol forms and keto forms is very small.
While the enol form is more stable in the gas phase than the keto
form by 6.011 kcal mol−1, the keto form is more stable than the
enol form by ∼3 kcal mol−1 in the solvent model. This stabiliz-
ation can be attributed to the hydrogen bonding of the keto
group with methanol. The relative energies are small enough to
be in equilibrium with the other counterpart even at room temp-
erature as shown in Table 3. But in our synthesis, the enol form
is predominant over the keto form. So, we optimized the tran-
sition state for the conversion; the energies are tabulated in
Table 3. The activation energies for keto–enol tautomerism are
198.255, 60.774 and 61.342 kcal mol−1 in the gas phase and
solvent models respectively. These energy barriers cannot be
attained at room temperature. So, only one form is predominant.
The spectroscopic studies also support this statement. In order to
investigate the keto–enol tautomerism, the 13C NMR spectrum
of 2f in DMSO was characterized and we found a group of reso-
nances in the aromatic region and the absence of a carbonyl
carbon signal in the δ ca. 170.0–210.0 ppm region, which
proved that there was no carbonyl carbon in the molecule. This
was the first confirmation that the molecule might exist in the
We initiated our investigation for the synthesis of pyrido[2,3-
b]indol-4(9H)-ones with various bases and solvents; the results
have been summarized in Table S2A.† The optimal reaction con-
dition for the cyclization of N-(3-acetyl-1-(substituted)-1H-indol-
2-yl)amides to pyrido[2,3-b]indol-4(9H)-ones was found to
involve the use of 5.0 equiv. of t-BuOK in THF at 70 °C. This
reaction condition proved to be generally applicable to a
wide range of N-(3-acetyl-1-(substituted)-1H-indol-2-yl)amides
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Table 1 Pd-catalyzed cross-coupling of 3-halo-2-formyl indoles, 3-carbonyl-2-haloindoles and amides
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enol form rather than the keto form. We recorded a solid state
13C NMR spectrum for the same product and it was further
confirmed to exist in the enol form as no carbonyl carbon peak
was observed. 13C NMR in the liquid state (DMSO) and solid
state are shown in Fig. S3a and S3b (ESI†)18 respectively. The
IR spectrum of the molecule (Fig. S4†)18 shows a broad peak at
Δνmax 3410 cm−1, assigned as an O–H vibration, and does not
show a peak for an N–H vibration (∼3300 cm−1). If the molecule
did exist in the keto form, interactions could be expected
between the protons labelled Ha and Hb and also between
Hb and Hc which should result in two cross peaks in the
NOESY spectrum. As both these peaks do not appear in the
NOESY spectrum (Fig. S3c†), we can assume that these inter-
actions are lacking and that the molecule does not exist in the
keto form.
Variable temperature powder X-ray diffraction measurements
(Fig. S3d†)18 also show the same peak pattern at all temperatures
measured from −30 °C to 110 °C (mp of 2f is 122 °C).
From these spectra, we concluded that there is no existence of
keto–enol tautomerism, and only the enol form exists exclusively
at room temperature. Although tautomerism is a difficult subject
to study in the gas phase, we recorded the GCMS of 2f
(Fig. S5†),18 which shows a fragment from the elimination
of M-OH (M-17). This indicates the presence of a OH group
in 2f.
After these spectroscopic confirmations and theoretical
calculations, we synthesized various 2-substituted-4-hydroxy-
α-carboline (2,9-substituted-9H-pyrido[2,3-b]indol-4-ol) deriva-
tives 2a–j successfully by using the above optimized reaction
conditions in good yields as shown in Table 2. The work-up
of these compounds was particularly facile as, with the
exception of 2d, all the compounds shown in Table 2 could be
isolated in pure form without the need to employ column
chromatography.
Next we focused on the synthesis of pyrimido[4,5-b] and
[5,4-b]indoles, which can be achieved using one of the follow-
ing processes: (a) the photochemical reaction of tetrazolo-
pyrimidines,17a or (b) intramolecular amination of 4-halo-5-
arylpyrimidines.17b–d To obtain the best reaction conditions for
the synthesis of pyrimido[4,5-b] and [5,4-b]indoles, we initially
tried a one-pot synthesis of highly substituted pyrimidoindoles.
Intrigued by these findings, we proceeded to optimize the reac-
tion conditions by using N-(3-acetyl-1-butyl-1H-indol-2-yl)acet-
amide (1s) as the model substrate. We initiated our investigation
with various ammonia sources and solvents as shown in
Table S3A†.18
To synthesize pyrimido[4,5-b] and [5,4-b]indoles, we explored
two methods (Table 4). Method A is a one-pot synthesis, in
which we directly added HCOONH4 in t-BuOH to the amidation
reaction mixture and continued the reaction at 110 °C. Method
B is a two step synthesis, in which we isolated the amide deriva-
tives 1a–u during the first step, and in the second step we added
HCOONH4 in t-BuOH at 110 °C. Of these two methods,
Method B is superior to Method A and using both of these we
synthesized 3a–t in excellent yields (Table 4). The possible
mechanisms for the reactions yielding pyrimidoindoles is
depicted in Scheme 1. In Scheme 1, HCOONH4 decomposes,
probably due to the application of heat, releasing NH3 which
generates the imine which further cyclises in the acid medium
due to the presence of excess of HCOONH4. Dehydration,
induced by acid and high temperature gives the required pyrimi-
doindoles (3a–t) in good to excellent yields. The work-up of
these compounds in Method B (step II) was also particularly
facile as all the compounds shown in Table 4, could be
isolated in pure form without the need to employ column
chromatography.
Table 2 Base catalyzed Camps cyclization and scope of the
reaction substratesa
The phenomenon of fluorescence has evolved to be a vital
exploratory technique in the various branches of science, impor-
tantly, in the areas of analytical, medical and biological sciences
etc.19 Among the various classes of organic π-systems, the
materials that absorb electromagnetic radiation by intramolecular
charge transfer (ICT) and emit from the corresponding photo
a Isolated yields.
Table 3 The total energy of the keto, enol and transition states at B3LYP/6-31+G(D) level of theory in the gas phase and in solvent
Method
Keto form (Hartree)
Enol form (Hartree)
Transition state energy (Hartree)
Activation energy (kcal mol−1
)
Gas phase
MeOH
THF
−726.6992284
−726.7225416
−726.8643483
−726.7088136
−726.7177769
−726.8604681
−726.3832852
−726.6256917
−726.7665929
198.255
60.774
61.342
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Table 4 Synthesis of pyrimido[4,5-b] and [5,4-b]indoles and substrate scopea
a Isolated yields.
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Scheme 1 Possible mechanisms for the reactions yielding pyrimido[4,5-b] and [5,4-b]indoles.
Table 5 Summary of optical data of the synthesized pyrimidoindoles
Compound
λmax (nm)
λem (nm)
Emax (cm−1
)
ΦF
3d
3f
3k
3l
3n
3p
3r
3s
311
315
315
330
332
313
314
314
408
417
406
416
404
415
454
416
24 509
23 980
24 630
24 038
24 752
24 096
22 026
24 038
0.4821
0.4924
0.4570
0.4927
0.4439
0.4989
0.5288
0.4946
λmax and Emax = absorption and emission maxima respectively.
in the applications of fluorescence studies, we studied the
UV-visible and emission spectral properties of pyrimido[4,5-b]
and [5,4-b]indoles (3d, 3f, 3h, 3k, 3l, 3n, 3p, 3r, 3s) in
DCM (10−5 mol dm−3) at 300 K. Absorptions and emissions
of these pyrimidoindoles are almost identical, as shown in
Fig. 2.
These pyrimidoindoles show absorption maxima (λmax) in the
region of 311–332 nm. The emission spectra of these pyrimi-
doindoles in DCM (10−5 mol dm−3) revealed band maxima in
the region of 400–454 nm and the corresponding excitation
wavelengths are shown in Fig. 2(b). The emission quantum
yields of the compounds 3d, 3f, 3h, 3k, 3l, 3n, 3p, 3r and 3s at
room temperature (using quinine sulphate in 1 NM H2SO4 as the
reference, whose quantum yield is known to be 0.54520) were
found to be 0.48, 0.49, 0.45, 0.49, 0.44, 0.49, 0.52, and 0.49
respectively as shown in Table 5. The molecules were excited at
the same optical densities where the of the sample intersects the
absorption curve of quinine sulphate.
The amide derivatives, such as N-(1-ethyl-3-formyl-1H-indol-
2-yl)benzamide, underwent a Michael reaction with nitro styrene
(5) in the presence of DABCO/MeCN at 70 °C to furnish the
functionalised dihydropyrido[2,3-b]indoles (4a–b) as shown in
Scheme 2. The reaction proceeds through Michael addition of
amide derivatives to nitro styrene followed by aldol conden-
sation. We carried out the same reaction using different bases
such as triethyl amine, piperidine and sodium ethoxide but
observed a faster and cleaner reaction with DABCO. These di-
Fig. 2 (a) UV–visible absorption spectra (b) emission spectra of pyri-
midoindoles in DCM.
excited state are most fascinating because of their remarkable
applications in the field of molecular electronics, integrated
photonic devices and non-linear optics,20 etc. Having an interest
hydropyrido[2,3-b]indoles (4a–b) were confirmed by 1H and 13
C
NMR spectra and thoroughly characterized by mass and elemen-
tal analysis.
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Scheme 2 Synthesis of dihydropyrido[2,3-b]indoles.
stirring according to the mentioned time in Table 1. At this
point, the reaction mixture was allowed to cool to room tempera-
ture, diluted with ethyl acetate, and the resulting solution was
filtered through celite, and concentrated under reduced pressure.
The crude material was purified by column chromatography on
silica gel (eluting with hexanes/ethyl acetate) to give the corre-
sponding coupled product.
Conclusions
In summary, we have described a new and efficient synthetic
methodology for the construction of biologically and pharmaceu-
tically active core structures containing pyrido[2,3-b]indoles,
dihydropyrido[2,3-b]indoles, pyrido[4,5-b] and [5,4-b]indoles.
A Pd-catalyzed amidation reaction was used for the C–N bond
formation at both the 3rd and 2nd positions of indoles using
various amide derivatives in good to excellent yields. By using
the amide precursors, we have synthesized a diverse range
of pyrido[2,3-b]indoles, pyrido[4,5-b] and [5,4-b]indoles under
very mild conditions with remarkably high yields. The keto–enol
tautomerism in hydroxy-α-carbolines has been investigated by
the DFT calculations. Fluorescence studies of pyrido[4,5-b] and
[5,4-b]indoles resulted in good quantum yields.
General procedure for the coupling of 2-halo-3-carbonylin-
doles and amide. An oven dried Ace Pressure tube with a Teflon
stir bar was charged with Pd2(dba)3 (0.50 mol%, 1.0 mol% Pd),
BINAP (0.25 mol%), amide (1.2 equiv.), Cs2CO3 (3.0 equiv.)
and 2-halo-3-carbonylindoles (1.0 equiv.) and if X = Br, toluene
(2.0 mL) or if X = Cl, t-BuOH (2.0 mL) and then capped with a
Teflon screw cap and the mixture was heated to 110 °C with stir-
ring according to the mentioned time in Table 1. At this point,
the reaction mixture was allowed to cool to room temperature,
diluted with ethyl acetate, and the resulting solution was filtered
through celite, and concentrated under reduced pressure. The
crude material was purified by column chromatography on silica
gel (eluting with hexanes/ethyl acetate) to give the corresponding
coupled product.
Experimental section
General information
The procedure does not require an inert atmosphere. All the
amide products obtained were purified by column chromato-
graphy using silica gel (100–200 mesh). Hexane was used as a
co-eluent. 1H and 13C NMR were recorded in 400 and 100 MHz
spectrometers respectively. The chemical shifts are reported in
General procedure for the coupling of 1-benzyl-3-chloro-1H-
indole-2-carbaldehyde and thiophene-2-carboxamide. An oven
dried Ace Pressure tube with a Teflon stir bar was charged with
Pd2(dba)3 (5.7 mg, 1.85 μmol, 2.0 mol% Pd), BINAP (5.0 mg,
0.92 μmol, 0.5 mol%), thiophene-2-carboxamide (28 mg,
0.07 mmol), base [Cs2CO3 (195 mg) or K3PO4 (127 mg) or
K2CO3 (83 mg) or t-BuOK (58 mg)], 1-benzyl-3-chloro-1H-
indole-2-carbaldehyde (0.05 g, 0.185 mmol) and t-BuOH
(2.0 mL) and then capped with a Teflon screw cap and the
mixture was heated to 110 °C with stirring for 8 h. At this point,
the reaction mixture was allowed to cool to room temperature,
diluted with ethyl acetate, and the resulting solution was filtered
through celite, and concentrated under reduced pressure. The
crude material was purified by column chromatography on silica
gel (eluting with hexanes/ethyl acetate) to give the corresponding
coupled product (1e) as pale yellow solid; m.p. 217–219 °C; IR
(KBr): 3259, 3120, 2845, 1763, 1669, 1632, 1529, 1427, 1372,
1
ppm downfield to TMS (δ = 0) for H NMR and relative to the
central CDCl3 resonance (δ = 77.0) for 13C NMR. IR spectra
were recorded on an FT/IR spectrometer. Elemental analyses
were recorded on a Flash EA 1112 analyzer in the School of
Chemistry, University of Hyderabad. Mass spectra were recorded
on either a VG7070H mass spectrometer using the EI technique
or a LCMS-2010 mass spectrometer. Melting points were
measured in open capillary tubes and are uncorrected.
General procedure for the coupling of 3-haloindole-2-carbal-
dehye and amide. An oven dried Ace Pressure tube with a
Teflon stir bar was charged with Pd2(dba)3 (if X = Cl, 1.0 mol%,
2.0 mol% Pd, if X = Br, 0.75 mol%, 1.5 mol% Pd), BINAP
(0.50 mol%), amide (1.2 equiv.), Cs2CO3 (3.0 equiv.), 3-halo-
indole-2-carbaldehyde (1.0 equiv.) and if X = Br, toluene
(1.0 mL) or if X = Cl, t-BuOH (2.0 mL) and then capped with a
Teflon screw cap and the mixture was heated to 110 °C with
1
1209, 1109, 1012, 915, 739 cm−1. H NMR (400 MHz, TMS,
CDCl3) δ: 10.62 (s, 1H), 10.22 (s, 1H), 7.95 (d, 1H, J = 8.0 Hz),
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7.83–7.82 (m, 1H), 7.64–7.63 (m, 1H), 7.33–7.31 (m, 1H),
7.30–7.24 (m, 5H), 7.18–7.15 (m, 1H), 7.09–7.07 (m, 2H), 5.62
(s, 2H). 13C NMR (100 MHz, TMS, CDCl3) δ: 185.6, 160.7,
142.3, 137.7, 136.0, 134.9, 134.4, 133.7, 133.1, 132.1, 130.8,
128.9, 128.3, 127.7, 126.8, 125.5, 123.2, 117.8, 111.6, 105.2,
49.4. LC-MS: m/z = 361 (M + H), positive mode; Anal. Calcd
for molecular formula C21H16N2O2S; C, 69.98; H, 4.47; N,
7.77%; found: C, 69.71; H, 4.38; N, 7.67%.
mode; Anal. Calcd for molecular formula C18H16N2O2; C,
73.95; H, 5.52; N, 9.58%; found: C, 73.85; H, 5.51; N, 9.45%.
General procedure for the coupling of 2-bromo-1-ethyl-1H-
indole-3-carbaldehyde and thiophene-2-carboxamide. An oven
dried Ace Pressure tube with a Teflon stir bar was charged with
Pd2(dba)3 (0.9 mg, 0.99 μmol, 1.0 mol% Pd), BINAP (0.31 mg,
0.49 μmol, 0.25 mol%), thiophene-2-carboxamide (30 mg,
0.239 mmol), base [Cs2CO3 (195 mg) or K3PO4 (127 mg) or
K2CO3 (83 mg) or t-BuOK (58 mg)], 2-bromo-1-ethyl-1H-
indole-3-carbaldehyde (0.2 g, 5.9 μmol) and t-BuOH (2.0 mL)
and then capped with a Teflon screw cap and the mixture was
heated to 110 °C with stirring for 8 h. At this point, the reaction
mixture was allowed to cool to room temperature, diluted with
ethyl acetate, and the resulting solution was filtered through
celite, and concentrated under reduced pressure. The crude
material was purified by column chromatography on silica gel
(eluting with hexanes/ethyl acetate) to give the corresponding
coupled product (1f) as pale yellow solid; m.p. 147–149 °C;
IR (KBr): 3252, 3159, 2876, 1778, 1669, 1612, 1466, 752,
N-(1-Butyl-2-formyl-1H-indol-3-yl)nicotinamide (1b). Yellow
solid; m.p. 196–198 °C; IR (KBr): 3329, 3222, 2917, 1792,
1
1662, 1522, 1460, 1329, 1262, 1209, 1111, 917, 725 cm−1. H
NMR (400 MHz, TMS, CDCl3) δ: 10.79 (s, 1H), 10.02 (s, 1H),
9.30 (s, 1H), 8.76 (s, 1H), 8.35 (d, 1H, J = 8.0 Hz), 7.99–7.97
(m, 1H), 7.39–7.28 (m, 4H), 4.11 (t, 2H, J = 8.0 Hz), 1.81–1.74
(m, 2H), 1.30–1.22 (m, 2H), 0.86 (t, 3H, J = 8.0 Hz). 13C NMR
(100 MHz, TMS, CDCl3) δ: 184.8, 165.0, 153.0, 149.0, 135.9,
134.5, 132.3, 128.7, 126.9, 125.0, 123.8, 123.4, 123.1, 119.1,
110.8, 44.9, 30.9, 20.1, 13.6. LC-MS: m/z = 322 (M + H), posi-
tive mode; Anal. Calcd for molecular formula C19H19N3O2; C,
71.01; H, 5.96; N, 13.08%; found: C, 71.22; H, 5.89; N,
13.15%.
1
717 cm−1. H NMR (400 MHz, TMS, CDCl3) δ: 10.67 (s, 1H),
10.09 (s, 1H), 7.92–7.91 (m, 2H), 7.61 (d, 1H, J = 8.0 Hz),
7.39–7.37 (m, 1H), 7.31–7.13 (m, 3H), 4.30 (q, 2H, J = 8.0 Hz),
1.46 (t, 3H, J = 8.0 Hz). 13C NMR (100 MHz, TMS, CDCl3) δ:
184.8, 160.8, 141.9, 137.5, 134.4, 134.1, 132.7, 130.9, 128.9,
125.4, 123.1, 123.0, 118.0, 110.8, 40.8, 14.1. LC-MS: m/z = 299
(M + H), positive mode; Anal. Calcd for molecular formula
C16H14N2O2S; C, 64.41; H, 4.73; N, 9.39%; found: C, 64.32; H,
4.79; N, 9.28%.
N-(1-Butyl-2-formyl-1H-indol-3-yl)acetamide
(1c). Orange
solid; m.p. 131–133 °C; IR (KBr): 3317, 3222, 2950, 1795,
1
1655, 1562, 1498, 1329, 1225, 1209, 1127, 919, 725 cm−1. H
NMR (400 MHz, TMS, CDCl3) δ: 9.99 (s, 1H), 9.61 (s, 1H),
8.02 (d, 1H, J = 8.0 Hz), 7.33–7.24 (m, 3H), 4.09 (t, 2H, J = 8.0
Hz), 2.28 (s, 3H), 1.79–1.71 (m, 2H), 1.33–1.25 (m, 2H), 0.91
(t, 3H, J = 8.0 Hz). 13C NMR (100 MHz, TMS, CDCl3) δ:
184.6, 170.5, 141.6, 134.3, 124.8, 123.8, 123.4, 123.0, 119.3,
110.7, 107.2, 44.4, 30.9, 20.1, 13.6. LC-MS: m/z = 259 (M +
H), positive mode; Anal. Calcd for molecular formula
C15H18N2O2; C, 69.74; H, 7.02; N, 10.84%; found: C, 69.81; H,
7.12; N, 10.76%.
General procedure for base-promoted cyclization to 2-substi-
tued-4-hydroxy-α-carbolines. An oven dried Ace Pressure tube
with a Teflon stir bar was charged with N-(3-acetyl-1-(substi-
tuted)-1H-indol-2-yl)amides (1.0 equiv) and t-BuOK (5.0 equiv)
in THF (6 mL). The pressure tube was then sealed with a Teflon
screw-cap and the reaction was placed in a preheated oil bath at
110 °C. The reaction mixture was stirred according to the men-
tioned time in Table 2 and then removed from the oil bath and
allowed to cool to room temperature. The reaction mixture was
then diluted with ethyl acetate. The resultant reaction mixture
was extracted with EtOAc (20 mL), washed with water (100 mL)
and dried over anhydrous Na2SO4. The solvent was removed
in vacuo to obtain the pure product (3a–3j). Hexane was added
and removed twice more before the product was dried in vacuo.
General procedure for the coupling of 3-bromo-1-ethyl-1H-
indole-2-carbaldehyde and benzamide. An oven dried Ace
Pressure tube with a Teflon stir bar was charged with Pd2(dba)3
(1.3 mg, 1.4 μmol, 1.0 mol% Pd), BINAP (0.60 mg, 0.9 μmol,
0.25 mol%), benzamide (28 mg, 0.239 mmol), base [Cs2CO3
(195 mg) or K3PO4 (127 mg) or K2CO3 (83 mg) or t-BuOK
(58 mg)], 3-bromo-1-ethyl-1H-indole-2-carbaldehyde (0.05 g,
0.199 mmol) and toluene (2.0 mL) and then capped with a
Teflon screw cap and the mixture was heated to 110 °C with stir-
ring for 8 h. At this point, the reaction mixture was allowed to
cool to room temperature, diluted with ethyl acetate, and the
resulting solution was filtered through celite, and concentrated
under reduced pressure. The crude material was purified by
column chromatography on silica gel (eluting with hexanes/ethyl
acetate) to give the corresponding coupled product (1a) as pale
brown solid; m.p. 113–115 °C; IR (KBr): 3352, 3217, 2920,
1789, 1653, 1519, 1454, 1390, 1222, 1210, 1109, 918,
9-Ethyl-2-methyl-9H-pyrido[2,3-b]indol-4-ol (2a). Pale yellow
solid; m.p. 117–119 °C; IR (KBr): 3429, 2927, 1658, 1026,
1003, 769, 725, 570, 528 cm−1 1H NMR (400 MHz, TMS,
.
DMSO-d6) δ: 10.88 (s, br, 1H), 7.94 (1H, d, J = 6.16 Hz), 7.54
(d, 1H, J = 8.0 Hz), 7.36–7.33 (m, 1H), 7.20–7.17 (m, 1H), 6.29
(s, 1H), 4.40 (q, 2H, J = 5.68 Hz), 2.68 (s, 3H), 1.29 (t, 3H, J =
5.72 Hz). 13C NMR (100 MHz, TMS, DMSO-d6) δ: 162.9,
149.5, 145.7, 137.6, 124.0, 121.7, 121.2, 120.0, 109.5, 106.8,
103.3, 36.0, 26.0, 14.3. LC-MS: m/z = 225 (M + H), negative
mode; Anal. Calcd for molecular formula C14H14N2O; C, 74.31;
H, 6.24; N, 12.38%; found: C, 74.42; H, 6.21; N, 12.28%.
1
727 cm−1. H NMR (400 MHz, TMS, CDCl3) δ: 9.87 (s, 1H),
9.62 (s, 1H), 7.94 (d, 2H, J = 8.0 Hz), 7.74 (d, 1H, J = 8.0 Hz),
7.62 (d, 1H, J = 8.0 Hz), 7.47–7.43 (m, 1H), 7.29–7.20 (m, 4H),
3.92 (q, 2H, J = 8.0 Hz), 1.22 (t, 3H, J = 8.0 Hz). 13C NMR
(100 MHz, TMS, CDCl3) δ: 189.2, 167.8, 136.2, 136.0, 134.8,
132.5, 132.4, 128.6, 127.8, 124.5, 123.0, 121.7, 121.6, 120.6,
110.4, 106.5, 38.2, 14.5. LC-MS: m/z = 293 (M + H), positive
9-Ethyl-2-phenyl-9H-pyrido[2,3-b]indol-4-ol (2b). Yellowish
orange solid; m.p. 152–154 °C; IR (KBr): 3425, 2924, 1635,
1
1572, 1456, 1379, 1338, 1178, 1109, 1022, 750 cm−1. H NMR
This journal is © The Royal Society of Chemistry 2012
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(400 MHz, TMS, CDCl3) δ: 11.73 (s, br, 1H), 8.24 (d, 1H, J =
6.0 Hz), 8.11 (d, 2H, J = 6.0 Hz), 7.50–7.40 (m, 4H), 7.39–7.32
(m, 1H), 7.31–7.29 (m, 1H), 7.06 (s, 1H), 4.61 (q, 2H, J =
6.0 Hz); 1.52 (t, 3H, J = 5.6 Hz). 13C NMR (100 MHz, TMS,
CDCl3) δ: 159.3, 155.3, 153.5, 140.0, 138.6, 128.9, 128.6,
128.5, 128.0, 127.1, 125.2, 122.9, 120.0, 119.7, 108.6, 102.8,
100.3, 36.3, 14.1. LC-MS: m/z = 289 (M + H), positive mode;
Anal. Calcd for molecular formula C19H16N2O; C, 79.14; H,
5.59; N, 9.72%; found: C, 79.24; H, 5.51; N, 9.65%.
Hexane was added and removed twice more before the product
was dried in vacuo.
4-Methyl-2-(thiophen-2-yl)-9H-pyrimido[4,5-b]indole
(3a).
Yellow solid; m.p. 127–129 °C; IR (KBr): 3050, 2856, 1919,
1852, 1680, 1570, 1462, 1252, 1170, 1100, 1028, 990,
1
752 cm−1. H NMR (400 MHz, TMS, CDCl3) δ: 11.0 (s, 1H,),
7.89–7.88 (m, 1H), 7.78–7.70 (m, 1H), 7.69–7.29 (m, 3H),
7.24–7.21 (m, 2H,), 2.73 (s, 3H). 13C NMR (100 MHz, TMS,
CDCl3) δ: 161.8, 158.4, 144.4, 137.2, 133.0, 132.3, 130.7,
128.4, 123.7, 122.7, 122.3, 119.3, 111.8, 101.0, 29.9; LC-MS:
m/z = 265 (M + H), positive mode; Anal. Calcd for molecular
formula C15H11N3S; C, 67.90; H, 4.18; N, 15.84%; found: C,
67.81; H, 4.23; N. 15.76%.
9-Butyl-2-phenyl-9H-pyrido[2,3-b]indol-4-ol
solid; m.p. 132–134 °C; IR (KBr): 3431, 2920, 1635, 1568,
1452, 1362, 1330, 1176, 1100, 1025, 756 cm−1 1H NMR
(2c). Brown
.
(400 MHz, TMS, DMSO-d6) δ: 11.63 (s, br, 1H), 8.27 (d, 1H,
J = 6.16 Hz), 8.00 (d, 2H, J = 4.0 Hz), 7.47–7.40 (m, 4H), 7.36
(d, 1H, J = 5.6 Hz), 7.31–7.28 (m, 1H), 6.98 (s, 1H), 4.53 (t,
2H, J = 8.0 Hz), 1.91–1.96 (m, 2H), 1.47–1.39 (m, 2H), 0.97 (t,
3H, J = 8.0 Hz). 13C NMR (100 MHz, TMS, DMSO-d6) δ:
160.2, 154.7, 153.4, 139.6, 138.8, 128.9, 128.6, 128.5, 128.0,
127.1, 125.1, 122.8, 120.0, 119.9, 108.9, 103.0, 100.8, 41.4,
31.1, 20.3, 13.8. LC-MS: m/z = 317 (M + H), positive mode;
Anal. Calcd for molecular formula C21H20N2O; C, 79.72; H,
6.37; N, 8.85%; found: C, 79.61; H, 6.31; N, 8.79%.
9-Butyl-2,4-dimethyl-9H-pyrimido[4,5-b]indole
(3b). Pale
purple or pink solid; m.p. 117–119 °C; IR (KBr): 3059, 2926,
2856, 1923, 1886, 1682, 1622, 1574, 1494, 1469, 1408, 1255,
1174, 1111, 1028, 999, 927, 794, 736 cm−1
.
1H NMR
(400 MHz, TMS, CDCl3) δ: 8.07 (d, 1H, J = 8.0 Hz), 7.53–7.50
(m, 2H), 7.35–7.26 (m, 1H), 4.43 (t, 2H, J = 8.0 Hz), 2.95 (s,
3H), 2.82 (s, 3H), 1.89–1.85 (m, 2H), 1.41–1.35 (m, 2H), 0.96
(t, 3H, J = 8.0 Hz). 13C NMR (100 MHz, TMS, CDCl3) δ:
163.7, 159.2, 155.8, 139.0, 126.3, 122.5, 120.9, 120.2, 109.7,
109.5, 41.1, 30.8, 29.7, 26.4, 20.2, 13.7. LC-MS: m/z = 254
(M + H), positive mode; Anal. Calcd for molecular formula
C16H19N3; C, 75.85; H, 7.56; N, 16.59%; found: C, 75.96; H,
7.52; N, 16.51%.
General procedure for the one-pot synthesis of pyrimido-
[4,5-b] & [5,4-b]indoles (Method A):. An oven dried Ace
Pressure tube with a Teflon stir bar was charged with Pd2(dba)3
(1.3 mg, 1.4 μmol, 1.0 mol% Pd), BINAP (0.18 mg, 2.9 μmol,
1.5 mol%), amide (86 mg, 0.07 mmol), base [Cs2CO3 (195 mg)
or K3PO4 (127 mg) or K2CO3 (83 mg) or t-BuOK (58 mg)],
3-halo-2-formylindoles or 2-halo-3-carbonylindoles (0.2 g,
5.9 μmol) and t-BuOH (2.0 mL) and then capped with a Teflon
screw cap and the mixture was heated to 110 °C with stirring
and the reaction was monitored by TLC. When the starting
material was completely consumed, the reaction mixture was
cooled to <80 °C and HCOONH4 (6.0 equiv) in t-BuOH (2 mL)
was added in one portion. The resulting mixture was heated back
to 110 °C and the reaction mixture was stirred for the according
time mentioned in Table 4. When the reaction was complete, the
reaction mixture was allowed to cool to room temperature,
diluted with ethyl acetate, and the resulting solution was filtered
through celite, and concentrated under reduced pressure. The
crude material was purified by column chromatography on silica
gel (eluting with hexanes/ethyl acetate) to give the corresponding
pyrimido[4,5-b] and [5,4-b]indole product.
9-Ethyl-2-phenyl-9H-pyrimido[4,5-b]indole
(3k). Greenish
brown solid; m.p. 114–116 °C, IR (KBr): 3061, 2978, 2930,
1668, 1622, 1581, 1556, 1493, 1467, 1433, 1400, 1359, 1224,
1140, 1091, 1066, 1024, 993, 923, 810, 769, 738, 698, 543,
1
449, 405 cm−1. H NMR (400 MHz, TMS, CDCl3) δ: 9.33 (s,
1H), 8.65 (m, 2H), 8.13 (d, 1H, J = 7.8 Hz), 7.58–7.50 (m, 5H),
7.39–7.35 (m, 1H), 4.59 (q, 2H, J = 7.2 Hz), 1.54 (t, 3H, J =
7.24 Hz). 13C NMR (100 MHz, TMS, CDCl3) δ: 160.8, 155.4,
148.0, 139.5, 138.7, 132.0, 130.1, 129.2, 128.4, 128.3, 127.3,
121.4, 121.1, 119.5, 112.5, 109.6, 36.2, 13.9. LC-MS: m/z = 275
(M + H), positive mode; Anal. Calcd for molecular formula
C18H15N3; C, 79.10; H, 5.53; N, 15.53%; found: C, 79.21; H,
5.58; N, 15.58%.
9-Ethyl-2-(pyridin-3-yl)-9H-pyrimido[4,5-b]indole (3l). Yel-
lowish orange solid; m.p. 92–94 °C; IR (KBr): 3042, 2935,
2920, 1610, 1562, 1552, 1530, 1485, 1475, 1390, 1200, 1132,
1085, 850, 795, 732, 709, 415 cm−1. 1H NMR (400 MHz, TMS,
CDCl3) δ: 9.79 (s, 1H), 9.27 (d, 1H, J = 2.0 Hz), 8.81 (d, 1H,
J = 7.84 Hz), 8.68 (s, 1H), 8.08 (d, 1H, J = 7.64 Hz), 7.54 (d,
1H, J = 7.32 Hz), 7.49–7.47 (m, 1H), 7.42–7.39 (m, 1H),
7.36–7.32 (m, 1H), 4.53 (q, 2H, J = 4.0 Hz), 1.50 (t, 3H, J =
8.0 Hz). 13C NMR (100 MHz, TMS, CDCl3) δ: 158.6, 155.1,
149.9, 147.9, 139.5, 135.5, 134.1, 132.8, 123.3, 121.5, 121.3,
119.2, 113.0, 109.7, 108.2, 36.3, 13.9. LC-MS: m/z = 275 (M +
H), positive mode; Anal. Calcd for molecular formula
C17H14N4; C, 74.43; H, 5.14; N, 20.42%; found: C, 74.32; H,
5.21; N, 20.36%.
General procedure for the one-pot synthesis of pyrimido-
[4,5-b] & [5,4-b]indoles (Method B). An oven dried Ace Pressure
tube with a Teflon stir bar was charged with either N-(3-carbo-
nyl-1-(substituted)-1H-indol-2-yl)amides or N-(1-(substituted)-2-
formyl-1H-indol-3-yl)amides (1.0 equiv) and HCOONH4 (6.0
equiv) in t-BuOH (6 mL). The pressure tube was then sealed
with a Teflon screw-cap and the reaction was placed in a pre-
heated oil bath at 110 °C. The reaction mixture was stirred for
according time mentioned in Table 4 and then removed from the
oil bath and allowed to cool to room temperature. The reaction
mixture was then diluted with ethyl acetate. The resultant reac-
tion mixture was extracted with EtOAc (20 mL), washed with
water (100 mL) and dried over anhydrous Na2SO4. The solvent
was removed in vacuo to obtain the pure product (3a–3t).
General procedure for the synthesis of dihydropyrido[4,5-b]-
indoles. A round bottom flask with a Teflon stir bar was charged
with N-(3-formyl-1-(substituted)-1H-indol-2-yl)amides (1.0 mmol),
5092 | Org. Biomol. Chem., 2012, 10, 5084–5093
This journal is © The Royal Society of Chemistry 2012

View Online
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to obtain 4a–b in good yields.
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(9-Ethyl-3-nitro-2-phenyl-2,9-dihydro-1H-pyrido[2,3-b]indol-1-
yl)(phenyl)methanone (4a). Pale yellow solid; m.p. 232–234 °C;
IR (KBr): 3063, 2926, 2854, 1670, 1612, 1508, 1464, 1352,
1
1269, 1095, 1018, 750, 690 cm−1. H NMR (400 MHz, TMS,
CDCl3) δ: 8.61 (s, 1H), 7.76–7.74 (m, 1H), 7.53–7.52 (m, 4H),
7.40–7.35 (m, 4H), 7.32–7.19 (m, 5H), 7.16 (s, 1H), 3.63 (q,
2H, J = 4.0 Hz), 0.91 (t, 3H, J = 7.32 Hz). 13C NMR (100 MHz,
TMS, CDCl3) δ: 169.7, 149.3, 139.6, 137.1, 136.4, 135.8,
133.1, 132.1, 128.9, 128.8, 128.7, 128.5, 127.1, 126.9, 126.6,
124.0, 123.4, 122.7, 118.6, 117.2, 112.4, 111.0, 102.1, 58.3,
39.6, 13.6. LC-MS: m/z = 424 (M + H), positive mode; Anal.
Calcd for molecular formula C26H21N3O3; C, 73.74; H, 5.00; N,
9.92%; found: C, 73.65; H, 5.00; N, 9.98%.
(9-Ethyl-3-nitro-2-phenyl-2,9-dihydro-1H-pyrido[2,3-b]indol-1-
yl)(thiophen-2-yl)methanone (4b). Orange solid; m.p. 217–
219 °C; IR (KBr): 2916, 1651, 1612, 1527, 1509, 1432, 1272,
1105, 1018 cm−1. 1H NMR (400 MHz, TMS, CDCl3) δ: 8.60 (s,
1H), 7.75–7.74 (m, 1H), 7.58–7.57 (m, 1H), 7.38–7.37 (m, 1H),
7.32–7.30 (m, 2H), 7.29–7.26 (m, 6H), 7.25–7.05 (m, 1H),
6.95–6.93 (m, 1H), 3.69 (q, 2H, J = 4.0 Hz), 0.87 (t, 3H, J =
4.0 Hz). 13C NMR (100 MHz, TMS, CDCl3) δ: 162.7, 138.6,
137.4, 136.2, 135.8, 135.7, 135.5, 133.4, 133.3, 132.6, 128.8,
127.8, 127.1, 126.7, 126.4, 123.9, 123.6, 122.7, 118.7, 111.0,
102.5, 58.3, 39.5, 13.6. LC-MS: m/z = 428 (M − H), negative
mode; Anal. Calcd for molecular formula C24H19N3O3S; C,
67.12; H, 4.46; N, 9.78%; found: C, 67.26; H, 4.51; N, 9.65%.
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Acknowledgements
We thank DST for financial support. A.S.K. thanks UGC for
SRF. P.V.A.R. thanks CSIR for JRF. A.S.K. thanks Narayana,
Durga Prasad, Kishore and Rajagopala Reddy for helping in
fluorescence and DFT studies.
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Org. Biomol. Chem., 2012, 10, 5084–5093 | 5093