An efficient synthesis of pyrido[1,2-a]indoles through aza-Nazarov type cyclization

Article abstract of DOI:10.1039/c4cc08783f

Transition metal free Br?nsted acid mediated synthesis of biologically important pyrido[1,2-a]indole scaffolds through aza-Nazarov type cyclization of readily available diaryl(2-pyridyl)methanol using formic acid has been developed. This methodology has b

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An Efficient Synthesis of Pyrido[1,2-a]indoles through
Aza-Nazarov Type Cyclization
Cite this: DOI: 10.1039/x0xx00000x
Iyyanar Karthikeyan,a Dhanarajan Arunprasatha and Govindasamy Sekar*a
Received 00th January 2014,
Accepted 00th January 2014
DOI: 10.1039/x0xx00000x
www.rsc.org/
range of biological activities such as anti-HIV,8 anti-inflammatory,9
Transition metal free Brønsted acid mediated synthesis of
biologically important pyrido[1,2- ]indole scaffolds through
aza-Nazarov type cyclization of readily available diaryl(2-
pyridyl)methanol using formic acid has been developed. This
methodology has been successfully extended to synthesize
atropisomers.
5-HT3 receptor antagonist,10 H3 receptor antagonist,11 usage as
molecular probes such as cytostatic,12 immunosuppressive,13 tubulin
polymerization inhibiting activities14 and conductivity nature in
material chemistry.15
a
C-N bond formation is an important tool in organic synthesis for the
synthesis of biologically and medicinally important nitrogen
containing heterocycles in single step manner from readily available
precursor.1,2 In addition, intramolecular CN bond formation is an
efficient process to synthesize polycyclic amines in single step
which is difficult by traditional synthetic methods.3 Functionalities
such as azides,4 amides5 and amines6 are used as amine source for C-
N bond formation. Due to readily available nature and stability,
utilizing pyridine nitrogen as amine source for intramolecular C-N
bond formation attracted the chemist for the synthesis of biologically
important nitrogen containing heterocycles.7
Scheme 1. Intramolecular C-N forming reaction for the synthesis of pyrido[1,2-
a]indoles.
By owing their biological important, the synthesis of these class of
compounds have been reported in the literature using transition
metal catalyst.16 Recently, Zhou et al. reported rhodium catalyzed C-
H activation of alkyne-tethered arylhydrazines for the synthesis of
pyrido[1,2-a]indoles (Scheme 1a).17 In 2011, Klumpp et al.
demonstrated metal free synthesis of pyrido[1,2-a]indoles from two
heterocycle containing triaryl carbinol using triflic acid (CF3SO3H)
(Scheme 1b).18 However, when single heterocycle containing triaryl
carbinol was subjected to this reaction condition, the starting
material got decomposed.18 To our continues effects towards
important nitrogen containing heterocycles synthesis,19 herein we
Fig
1. Some representative example for pyrido[1,2-a]indole containing
biologically important molecules
Pyrido[1,2-a]indole, indolo[2,1-a]quinolone and pyrimido[1,2-
a]indole are nitrogen containing heterocycles frequently found in
several natural products (Figure 1). These molecules show broad
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report metal free efficient synthesis of pyrido[1,2-a]indoles using column21 and HPLC chromatograms of these molecules are shown in
formic acid from readily available triaryl methanol in single step Figure 3.22 We strongly believe that the axial chirality of these
(Scheme 1c). In this aza-Nazarov type cyclization process, pyridine important molecules will find prominent position in the field of
nitrogen of triaryl methanol is acting as nitrogen source to give medicinal chemistry.
pyrido[1,2-a]indoles through aza-Nazarov type cyclization.
Diphenyl(pyridin-2-yl)methanol 1a was chosen as model substrate
for this cyclization reaction and formic acid (3 mL) as solvent as
well as Brønsted acid source to achieve aza-Nazarov type cyclization
and the results are summarized in Table 1. Interestingly, this reaction
o
gave 95% of cyclized product 2a at 130 C (entry 1). To investigate
the effect of Brønsted acid, various Bronsted acids such as pivalic
acid (PivOH), acetic acid (AcOH) and trifluroacetic acid (TFA) were
used as acid source as well as solvent. Among them, only acetic acid
mediated reaction gave 31% isolated yield of 2a after 8 hours (entry
3). To improve the efficiency of this reaction, the reaction was
further carried out in various temperatures and a maximum yield of
o
96% was isolated at 120 C in 6 hours. Choosing this as optimized
reaction conditions, the substrate scope for this reaction was
explored and the results are summarized in Table 2.20
Table 1. Optimization for aza-Nazarov type cyclization
Fig 2. Substrate scope for aza-Nazarov type cyclization reactiona
All the triarylmethanols having pyridine as well as quinoline
moieties were successfully converted to corresponding cyclized
product in good to excellent yields (Table 2). Substrates containing
functional groups such as methoxy, chloro, thiomethyl, alkyl and
fluoro in aromatic rings were well tolerated. Interestingly,
pyrimidine containing triarylmethanol was also converted to
corresponding aza-Nazarov type cyclized product 2b in excellent
yield under optimized reaction conditions (entry 2). Substitution on
pyridine ring that is 6-methylpyridine containing triarylmethanol 1f
was successfully converted to corresponding intramolecular C−N
bond formed product 2f (entry 6). In addition, p-SMe 1g and p-Cl 1h
group containing triaryl methanols were underwent smoothly and
gave 93% and 97% of yield respectively (entries 7 and 8). Even, p-F
1l, p-Et 1m and p-tert-butyl 1n containing triarylmethanols were
also successfully converted to corresponding cyclized product with
good to excellent yield (entries 11, 12 and 13).
Scheme 2. Metal free synthesis of axial chiral molecules
When bulky group substituted starting materials such as two 1-
naphthyl groups containing triarylmethanol 1o and o-tolyl group
containing triarylmethanol 1p were converted to corresponding aza-
Nazarov type cyclized products in excellent yields (Scheme 2). The
naphthyl substituted aza-Nazarov type cyclized product 2o was
further confirmed by solid state X-ray analysis (Figure 2).
Interestingly, both these molecules 2o and 2p have shown axial
chirality. The chirality of 2o and 2p were further confirmed by high
pressure liquid chromatography (HPLC) using chiral OD-H
Figure 3. Single crystal X-ray structure of 2o (CCDC No. 994568, 30% probability
ellipsoid).
2 | Chem. Commun., 2014, 00, 1-3
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For N-heterocycle synthesis through intramolecular C-N bond, see (a)
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Figure 4. HPLC chromotogram of 2o (a) and 2p (b).
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Scheme 3. Plausible reaction mechanism for the formic acid mediated aza-Nazarov
type cyclization
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Conclusions
In conclusion, formic acid mediated intramolecular azo-Nazarov
cyclization reaction was developed for the synthesis of pyrido[1,2-
a]indole derivatives. This methodology provides wide range of
substrate scope such as pyridine, quinoline and pyrimidine
containing triaryl methanol were successfully converted to
corresponding aza-Nazarov type cyclized products in good to
excellent yield. Under the optimized reaction conditions a wide
range of functional groups such as thiomethyl, methoxy, chloro,
fluoro etc. were well tolerated and all of them gave good to excellent
yield. Very interestingly, axial chirality was found when substrate
having bulky substitution at ortho position of the cyclized products.
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Acknowledgements
We thank DST (project No.: SB/S1/OC-72/2013) and DST Nano
mission (SR/NM/NS-1034/2012(G)) New Delhi for financial
support. I. K and D. A thank CSIR, India for senior research
fellowship and junior research (SPM) fellowship respectively.
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4202, E-mail: gsekar@iitm.ac.in.
Electronic Supplementary Information (ESI) available: Experimental
procedure for intramolecular C-H amination and tertiary alcohol
formation reaction and copy of 1H NMR and 13C NMR spectra were
given in SI. This material is available free of charge via the Internet at
http://pubs.acs.org.. See DOI: 10.1039/c000000x/
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20 Diarylalkylmethanols such as methyl, iso-propyl and tert-butyl
containing substrates did not undergo for aza-Nazarov type cyclization
and unsymmetrical triarylmethanols gave mixture of cyclized product.
21 Determined using chiral OD-H column, 0.5 mL/min,
IPA:hexanes for compound 2n and chiral OD-H column 0.5 mL/min,
2 % IPA:hexanes for compound 2o
3 %
.
22 When we tried to resolve compound 2k by HPLC using chiral
columns (totally 9 columns were used), this compound 2k did not
resolve by any chiral column. So we are assuming that the compound
2k may not be chiral compound.
4 | Chem. Commun., 2014, 00, 1-3
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