Annulation of imidazo[1,2-: A] pyridines under metal-free conditions

Article abstract of DOI:10.1039/d0nj04521g

A base promoted protocol for the synthesis of benzo[a]imidazo[5,1,2-cd]indolizines from 2-arylimidazo[1,2-a]pyridines and benzyne precursors under metal-free conditions has been developed. Without a transition metal, double C(sp2)-H activation of 2-phenylimidazo[1,2-a]pyridines under basic conditions was achieved. This method is also applicable for the annulation of imidazo[1,2-a]pyrimidine and naphthylamine under the same conditions. These annulated molecules showed fluorescence characteristics and hence their photo physical properties were evaluated. This journal is

Full text of DOI:10.1039/d0nj04521g

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Annulation of Imidazo[1,2-a]pyridines Under Metal-free
Conditions
Rashmi Semwala, Abhisek Joshia, Rahul Kumara and Subbarayappa Adimurthy*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
rhodium are dominating the field, the development of improved
protocols under metal-free conditions to access such scaffolds are
admirable in synthetic organic chemistry.
Base
promoted
protocol
for
the
synthesis
of
benzo[a]imidazo[5,1,2-cd]indolizines from 2-arylimidazo[1,2-
a]pyridines and benzyne precursors under metal-free conditions
has been developed. Without transition metal double C(sp2) −H
activation of 2-phenylimidazo[1,2-a]pyridines under basic
conditions were achieved. The method also applicable for the
annulation of imidazo[1,2-a]pyrimidine and naphthylamine under
the same conditions. These annulated molecules showed
fluorescence characteristics and hence photo physical properties
were evaluated.
Result and discussion
To this end, in continuation of our research on the
functionalization14 and annulation of fused heterocycles,15 we
envisioned our studies on the annulation of imidazo[1,2-a]pyridines
using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate as
benzyne precursor under metal-free conditions (Scheme 1).
a
Introduction
Heteroaromatic polycyclic systems have received considerable
attention owing to their potential applications in the materials
science, medicine and as organic electronic materials.1 Accordingly,
the development of new methodologies to access these valuable
molecules continues to be of great importance in synthetic organic
chemistry. To construct such polycyclic heteroarenes, one of the
best method is through the annulation of aza-fused heterocycles
Scheme 1.
Initially to screen the reaction conditions, 2-phenylimidazo[1,2-
a]pyridine 1a was chosen as a model substrate for the annulation
with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate 2a in
acetonitrile as solvent and K2CO3 as base at room temperature for
24 h, under these conditions the annulated product was not
observed (Table 1, entry 1). The same reaction was performed with
CsF as base, 14% of annulated product 3a was obtained (entry 2).
Under the same conditions, use of NaCl as an additive, the desired
product yield was increased to 35% (entry 3). As the yield was
increased in presence of additive, we screened different additives
(NBS, KBr, NaI and 18-crown-6-ether) among these, 18-crown-6-
ether gave 55% yield of the desired product (entries 4–7). With 18-
crown-6-ether as additive, next different bases (KF, KOtBu, NaOtBu
& K2CO3) were verified. Under these conditions either low yield or
no reaction was observed (Table 1, entries 8–11). Keeping 18-crown-
6-ether as additive and K2CO3 as base, other solvents were screened
(Table 1, entries 12–18). Further altering of either additive or base,
the yield of the desired product was declined or no reaction was
observed (Table 1, entry 19–23). When the reaction was performed
at 45⁰C, the desired product 3a was isolated in 95% yield (entry 24).
Further, to reduce the reaction time, the same reaction was
conducted at 60⁰C, but the reaction completion needs 24 h, as
such as
quinolines,2 aminoquinolines,3
naphthapyrans,4
phenanthroimidazoles,5 and naphthyridines6 have been described.
In particular, annulation of imidazo[1,2-a]pyridine derivatives have
been extensity explored in last decade due to their multifunctional
applications spanning from biological activities,7 fluorescent
probes,8 organic dyes,9 chemosensors,10 and to luminescent
materials.11 Recently, annulation of imidazo[1,2-a]pyridines with
benzyne precursors12 and with alkynes13 were reported. Despite the
significance of these methods on the annulation of imidazo[1,2-
a]pyridines, the requirement of microwave conditions and limited
substrate scope was observed.12a,b In some cases the precious metal
catalyst such as palladium12c and rhodium13 were essential to
achieve the efficient transformations. Although palladium and
aAcademy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals
Research Institute, G. B. Marg, Bhavnagar-364 002. Gujarat, INDIA.
E-mail: adimurthy@csmcri.res.in†
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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monitored by TLC (entry 25). Further, with 18-crown-6-ether as an as pyridyl rings in the 2-phenyl imidazo[1, 2-a]pyridines were reacted
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additive, the reactions were performed with CsF as a base in DCM, smoothly with 2a and afford the corresponding annulated products
DOI: 10.1039/D0NJ04521G
acetone and 1,4 dioxane as a solvents but low yield of the product 3i–p in good yields (60-83%). Low yield (3q) was observed for the
was observed in these cases (entry 26-28). The reaction was also annulation of para-substituted imidazopyridines 7-chloro-2-(4-
checked under microwave irradiation at room temperature but only chlorophenyl)imidazo[1,2 a]pyridine]. In addition, debromination
36 % yield of 3a was obtained (entry 29). Hence the conditions of was also observed for the corresponding starting substrate 6-bromo-
entry 24 were fixed as optimum for the further substrate scope.
2-(4-ethylphenyl)imidazo[1,2-a]pyridine under the present
conditions and products 3c formation was observed in 54% yield.[16]
The C2 and C3 unsubstituted imidazo[1,2-a]pyridines were also
subjected to the optimised reaction conditions with the benzyne
precursor 2a, and obtained the annulated products 3r–t in
moderate to good yields (45-78%).
Table 1. Optimisation of conditionsa
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Then we focused on the reaction of substituted benzyne precursors
with the variety of imidazo[1, 2-a]pyridines under the same reaction
conditions. Methyl and methoxy benzyne precursors reacted with
different imidazo[1, 2-a]pyridines and afford the annulated
products 3u–3aa in 65% -80% yields. The reaction of methyl
substituted benzene precursors with different imidazypyridines, we
obtained two structural isomers together (not separable by column
chromatography). One of the alkyl substituted substrate 2-(tert-
butyl)imidazo[1,2-a]pyridine was also reacted with 2a and obtained
the desired annulated product 3ab in 62% yield. Further to ascertain
the scope of the present annulation methods, we subjected the
other heterocycles such as imidazo[1,2-a]pyrimidines and amino
naphthalenes (Scheme 2). Under the same optimised conditions, 2-
phenylimidazo[1,2-a]pyrimidine 4a was reacted with benzyne
Table 2. Substrate Scope for annulation of imidazo[1,2-a]pyridinesa
aConditions: 1a (0.2 mmol); 2a (1-2.0 mmol); additive; base;
solvent (2.0 mL), 24 h, isolated yield at room temperature.
bReaction at 45⁰C. cReaction at 60⁰C, dReaction under microwave
irradiations at room temperature, 1.0 h.
With the above optimized conditions (Table 1, entry 24), the scope
and limitations of annulated imidazo[1,2-a]pyridines was
established (Table 2). First, we examined the reaction of 2-
arylimidazo[1,2-a]pyridines
bearing
electron-donating
and
withdrawing groups (OMe, Et, F, and CN,) at the para–position of the
phenyl ring, were reacted smoothly with the benzyne precursor 2a,
and afford the corresponding annulated products 3b–e in good
yields (69–82%). The presence of such groups at ortho- position of
the phenyl ring were also gave the annulated products 3f–h in
moderate to good yields (66–71%). Further debromination was
observed for the substrate 2-(2-bromophenyl)imidazo[1,2-
a]pyridine and the product 3a was observed in 55 % yield.16
aConditions: Imidazo[1,2-a]pyridine
1 (0.2 mmol); benzyne
precursor 2 (0.4 mmol); 18-crown-6-ether (0.4 mmol); K2CO3(0.4
mmol); acetone (2.0 mL), 45⁰C, 24 h, isolated yield. bYield obtained
c
at gram scale. Debrominated product 3a and 3c was observed.
dStructural isomers obtained.
Further, the presence of electron-rich or electron-deficient groups
(Me, OMe, Et, Cl, and F) at different positions on the phenyl as well
2 | J. Name., 2012, 00, 1-3
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precursors 2a and obtained the desired annulated product 6a in
good yield (70%). The reaction of the benzyne precursor 2a, with
naphthalen-1-amine 5a gave an interesting product 7H-
benzo[kl]acridine 7 in 60% yield under the same optimised
conditions. However, the benzyne precursors 2b and 2c afford N-
aryl naphthyl amines 8 and 9 in 65% and 68% yields respectively.
Probably due to the substituent effects, 2b and 2c didn’t yield the
cyclized products.
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To get insights of the reaction mechanism, some control
experiments were conducted (Scheme 3). To know the reaction
pathway, the reaction of 1a and 2a was subjected to the optimised
conditions in presence of radical scavengers TEMPO and BHT. Under
these conditions, the desired annulated product 3a was obtained in
45% and 69% yields respectively. These reactions suggest that, the
present reaction may not proceed through radical path. Further,
when 5-methyl-2-phenylimidazo[1,2-a]pyridine 10 was reacted
with 2a under the optimised conditions, as C-5 position of 10 was
substituted by methyl group, it prevents the cyclisation and even
does not yield the C-3 substituted product 11, the starting substrate
1a remain unreacted.12a
Scheme 4. Proposed mechanism
In the presence of base and 18-crown-6-ether, 2a generates benzyne
as intermediate in situ. The reaction of 1a with benzyne may
generate [8+2] cycloaddition adduct A.12a Subsequent
dehydrogenation of A, yield the desired annulated product 3a.
Due to high fluorescence characteristics of annulated
imidazoheterocycles we evaluated the photo physical properties of
selected imidazopyridine derivatives which shown intense
fluorescence. Emission spectra of 10 μM solution of these
fluorophores in DCM were recorded by exciting at respective
wavelength (Figure 1), and it was observed that all the probes
showed emission in the visible region at 420−600 nm (Figure 1). The
quantum yields (Φf) of these fluorophores were found to be
0.33−0.68.
Scheme 2. Annulation of imidazo[1,2-a]pyrimidine and
naphthylamine
Further, 12 was subjected to the optimised conditions with 2a, the
expected product 13 was not observed. It suggests that, first
arylation at C-5 followed by the annulation/cyclisation at C-3
position of imidazo[1,2-a]pyridine ring may take place under the
present conditions. Hence both C-3 and C-5 positions should be free
for the annulation of imidazo[1,2-a]pyridines.
F
Figure 1. Normalized absorption (a) and normalized emission
(b) spectra of selected imidazopyridines.
Conclusion
We have developed a base promoted protocol for the synthesis of
benzo[a]imidazo[5,1,2-cd]indolizines
from
2-arylimidazo[1,2-
a]pyridines and benzyne precursors under metal-free conditions.
Without transition metal double Sp2 C−H activation of 2-
phenylimidazo[1,2-a]pyridines under basic conditions were
achieved. The method also applicable for the annulation of
imidazo[1,2-a]pyrimidine and naphthylamine under the same
conditions. The presence of K2CO3 and 18-crown-6-ether are the
best combination to obtain good yields of desired annulated
products.
Scheme 3. Control experiments
Based on the control experiments and literature reports,12,13
plausible reaction mechanism has been proposed (Scheme 4).
a
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Multiple C-H Activation and Annulation, Angew. Chem., Int. Ed.
Acknowledgements
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2014, 53, 9889. sssssssss
DOI: 10.1039/D0NJ04521G
CSIR-CSMCRI communication No. 125/2020. S. R. is thankful to AcSIR 7. J. Koubachi, S. E. Kazzouli, M. Bousmina, G. Guillaumet,
for their Ph.D. enrolment and the “Analytical Discipline and
Centralized Instrumental Facilities” for providing instrumentation
facilities. S. R. also thankful to DST, New Delhi for the award of
Functionalization of Imidazo[1,2-a]pyridines by Means of Metal-
Catalyzed Cross-Coupling Reactions, Eur. J. Org. Chem. 2014,
5119.
INSPIRE fellowship. Manpreet Singh and Ratish R. Nair for helping us 8. (a) N. Shao, G. X. Pang, C. X. Yan, G. F. Shi, Y. J. Cheng, Reaction
in the determination of photophysical properties of fluorophores.
We are thankful to DST, Government of India (EMR/2016/000010 &
EMR/2016/004944) for the research grants and CSIR-CSMCRI (MLP-
0027) for the partial financial support.
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Conflicts of interest
There are no conflicts of interest to declare.
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Heterocycles, J. Org. Chem. 2014, 79, 1277. (i) D. C. Mohan, D. R.
Reddy, S. N. Rao and S. Adimurthy, Copper(I) Iodide-Catalysed
Aerobic Oxidative Synthesis of Imidazo [1,2-a]pyridines from 2-
Aminopyridines and Methyl Ketones, Adv. Synth. Cat. 2013, 355,
2217. (j) D. C. Mohan, S. N. Rao and S. Adimurthy, Synthesis of
Imidazo[1,2‑a]pyridines: “Water-Mediated” Hydroamination
and Silver-Catalyzed Aminooxygenation, J. Org. Chem. 2013, 78,
1266. (k) K. C. Chunavala, G. Joshi, E. Suresh and S. Adimurthy,
Thermal and Microwave-Assisted Rapid Syntheses of Substituted
Imidazo[1,2-a]pyridines Under Solvent- and Catalyst-Free
Conditions. Synthesis, 4, 2011, 635.
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synthesis
of
2,6−disubstituted
pyridines
through
denitrogenation of pyridotriazoles and 3,8−diarylation of
imidazo[1,2-a]pyridines, Chem. Commun., 2019, 55, 10888. (c) R.
Semwal, C. Ravi, R. Kumar, R. Meena and S. Adimurthy, Sodium
Salts (NaI/NaBr/NaCl) for the Halogenation of Imidazo- Fused
Heterocycles, J. Org. Chem. 2019, 84, 792. (d) R. Semwal, C. Ravi,
S. Saxena, S. Adimurthy, Copper-Catalyzed Multicomponent
Reactions (MCRs) for Disulfenylation of and Arylhalides and
Intramolecular Cyclization of Haloimidazo[1,2‑a]pyridines, J.
Org. Chem. 2019, 84, 14151. (e) R. Kumar, C. Ravi, D. Rawat and
S. Adimurthy, Base-Promoted Transition-Metal-Free Arylation of
Imidazo- Fused Heterocycles with Diaryliodonium Salts, Eur. J. 16. Control experiments confirmed, that, the annulation followed by
Org. Chem. 2018, 1665. (f) C. Ravi, S. N. Rao, A. Joshi, and S.
Adimurthy, Visible-light-promoted selective C–H amination of
heteroarenes with heteroaromatic amines under metal-free
conditions, Org. Biomol. Chem. 2017, 15, 9590. (g) C. Ravi, A.
Joshi, and S. Adimurthy, C3 Sulfenylation of N-Heteroarenes in
Water under Catalyst- Free Conditions, Eur. J. Org. Chem. 2017,
3646. (h) C. Ravi, S. Adimurthy, Synthesis of imidazo[1,2-
a]pyridines: C-H functionalization in the direction of C-S bond
formation, Chem. Rec. 2017, 17, 1. (i) C. Ravi, N. N. K. Reddy, V.
Pappula, S. Samanta, S. Adimurthy, Copper-Catalyzed Three-
Component System for Arylsulfenylation of Imidazopyridines
with Elemental Sulfur, J. Org. Chem. 2016, 81, 9964. (j) C. Ravi,
D. C. Mohan, and S. Adimurthy, Dual Role of p–Tosylchloride:
Copper–Catalyzed Sulfenylation and Metal free Methylthiolation
of Imidazo [1, 2–a] pyridines, Org. Biomol. Chem. 2016, 14, 2282.
(k) C. Ravi, D. C. Mohan, S. Adimurthy, N‑Chlorosuccinimide-
Promoted Regioselective Sulfenylation of Imidazoheterocycles
at Room Temperature, Org. Lett. 2014, 16, 2978. (l) D. C. Mohan,
S. N. Rao, C. Ravi, S. Adimurthy, Copper(I) Iodide Catalyzed
Aerobic Oxidative C-N and C-S bond formations through C-H
Activation: Synthesis of Functionalized Imidazo [1,2-a]pyridines,
Asian J. Org. Chem. 2014, 3, 609.
dehalogenation take place but not the vice-versa (see supporting
information for details).
15. (a) C. Ravi, S. Samanta, D. C. Mohan, N. N. K. Reddy, and S.
Adimurthy, Synthesis of Functionalized Pyrazolo[1,5-a]pyridines:
[3+2] Cycloaddition of N-Aminopyridines and α,β-Unsaturated
Carbonyl Compounds/Alkenes at Room Temperature, Synthesis,
2017, 49, 2513. (b) A. Joshi, D. C. Mohan, S. Adimurthy, Copper-
Catalyzed Denitrogenative Transannulation Reaction of
Pyridotriazoles: Synthesis of Imidazo[1,5‑a]pyridines with
Amines and Amino Acids, Org. Lett. 2016, 18, 464. (c) D. R.
Reddy, S. Samanta, and S. Adimurthy, Copper−catalyzed
C(sp3)−H functionalization of ketones with vinyl azides:
Synthesis of substituted−1H−pyrroles, Org. Biomol. Chem. 2015,
13, 10113. (d) D. C. Mohan, C. Ravi, P. Venkatanarayana and S.
Adimurthy, Synthesis of Indolizines Through Oxidative Linkage of
C-C and C-N bonds from 2-Pyridylacetates, J. Org. Chem. 2015,
80, 6846. (e) C. Ravi, D. C.
Mohan, N. N. K. Reddy, S. Adimurthy, Substrate selective synthesis
of pyrazolo[1, 5-a]pyridines through [3+2] cycloaddition of N-
aminopyridines and β-nitro styrenes, RSC Advances 2015, 5,
42961. (f) D. C. Mohan, S. N. Rao, C. Ravi, and S. Adimurthy,
Copper-Catalyzed Aerobic Oxidative Amination of C(sp3)-H
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COMMUNICATION
Journal Name
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View Article Online
DOI: 10.1039/D0NJ04521G
Annulation of Imidazo[1,2-a]pyridines
Under Metal-free Conditions
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Rashmi Semwala, Abhisek Joshi, Rahul Kumara and Subbarayappa
Adimurthy*a
aAcademy of Scientific & Innovative Research, CSIR–Central Salt &
Marine Chemicals Research Institute, G. B. Marg, Bhavnagar-
364002. Gujarat, INDIA.E-mail: adimurthy@csmcri.res.in
6 | J. Name., 2012, 00, 1-3
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