Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 9;9(50):49980-49985.
doi: 10.1021/acsomega.4c09295. eCollection 2024 Dec 17.

Metal-Free Synthesis of Functionalized Indolizines via a Cascade Michael/SN2/Aromatization Reaction of 2-Alkylazaarene Derivatives with Bromonitroolefins

Kangbiao Chen  1 , Rui Zhou  2 , Gaofeng Zhu  2 , Lei Tang  2 , Lu Huang  1 , Qing He  2
Affiliations

Metal-Free Synthesis of Functionalized Indolizines via a Cascade Michael/SN2/Aromatization Reaction of 2-Alkylazaarene Derivatives with Bromonitroolefins

Kangbiao Chen et al. ACS Omega. .

Abstract

A transition metal-free domino Michael/SN2/aromatization annulation of 2-pyridylacetates with bromonitroolefins has been developed. A wide range of substrates containing various substituted groups was compatible with the present methodology and afforded functionalized indolizines with moderate to excellent yield (up to 99% yield). In addition, the potential practicality of the method stood out through scale-up reactions and further transformations to other valuable compounds. In our view, this study is an essential complement for the rapid construction of indolizine derivatives through a metal-free strategy.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected bioactive molecules containing indolizine scaffolds.
Scheme 1
Scheme 1. Synthetic Strategies for Indolizines and Our Design
Scheme 2
Scheme 2. Substrate Scope for the Domino Cyclization of 2-Alkylazaarene 1a with Bromonitroolefins
Unless noted otherwise, reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol), and Na2CO3 (1.5 equiv) in THF (1.0 mL) at 80 °C in a sealed tube for 24 h. Isolated yields. The reaction time is 48 h.
Scheme 3
Scheme 3. Substrate Scope for the Domino Cyclization of 2-Alkylazaarenes with Bromonitroolefin 2a
Unless noted otherwise, reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol), and Na2CO3 (1.5 equiv) in THF (1.0 mL) at 60 °C in a sealed tube for 24 h. Isolated yields. The reaction time is 48 h.
Scheme 4
Scheme 4. Gram-Scale Experiment and Further Transformations
Scheme 5
Scheme 5. Possible Reaction Pathway
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. For selected reviews, see:

    2. Heravi M. M.; Zadsirjan V. Prescribed drugs containing nitrogen heterocycles: an overview. RSC Adv. 2020, 10, 44247–44311. 10.1039/D0RA09198G. - DOI - PMC - PubMed
    3. Obaid R. J.; Mughal E. U.; Naeem N.; Al-Rooqi M. M.; Sadiq A.; Jassas R. S.; Moussa Z.; Ahmed S. A. Pharmacological significance of nitrogen-containing five and six-membered heterocyclic scaffolds as potent cholinesterase inhibitors for drug discovery. Process Biochem. 2022, 120, 250–259. 10.1016/j.procbio.2022.06.009. - DOI
    4. Kumar A.; Singh A. K.; Singh H.; Vijayan V.; Kumar D.; Naik J.; Thareja S.; Yadav J. P.; Pathak P.; Grishina M.; Verma A.; Khalilullah H.; Jaremko M.; Emwas A. H.; Kumar P. Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective. Pharmaceuticals 2023, 16, 299.10.3390/ph16020299. - DOI - PMC - PubMed
    1. Hagishita S.; Yamada M.; Shirahase K.; Okada T.; Murakami Y.; Ito Y.; Matsuura T.; Wada M.; Kato T.; Ueno M.; Chikazawa Y.; Yamada K.; Ono T.; Teshirogi I.; Ohtani M. Potent Inhibitors of Secretory Phospholipase A2: Synthesis and Inhibitory Activities of Indolizine and Indene Derivatives. J. Med. Chem. 1996, 39, 3636–3658. 10.1021/jm960395q. - DOI - PubMed
    2. Dennis E. A.; Cao J.; Hsu Y.-H.; Magrioti V.; Kokotos G. Phospholipase A2 Enzymes: Physical Structure, Biological Function, Disease Implication, Chemical Inhibition, and Therapeutic Intervention. Chem. Rev. 2011, 111, 6130–6185. 10.1021/cr200085w. - DOI - PMC - PubMed
    3. Sharma V.; Kumar V. Indolizine: a biologically active moiety. Med. Chem. Res. 2014, 23, 3593–3606. 10.1007/s00044-014-0940-1. - DOI
    1. Ghinet A.; Abuhaie C. M.; Gautret P.; Rigo B.; Dubois J.; Farce A.; Belei D.; Bîcu E. Studies on indolizines. Evaluation of their biological properties as microtubule-interacting agents and as melanoma targeting compounds. Eur. J. Med. Chem. 2015, 89, 115–127. 10.1016/j.ejmech.2014.10.041. - DOI - PubMed
    2. Moon S.-H.; Jung Y.; Kim S. H.; Kim Y. Synthesis, characterization and biological evaluation of anti-cancer indolizine derivatives via inhibiting β-catenin activity and activating p53. Bioorg. Med. Chem. Lett. 2016, 26, 110–113. 10.1016/j.bmcl.2015.11.021. - DOI - PubMed
    1. Sharma P.; Kumar A.; Sharma S.; Rane N. Studies on synthesis and evaluation of quantitative structure–activity relationship of 5-[(3′-chloro-4′,4′-disubstituted-2-oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]aza-phospholo[1,5-a]pyridinyl phosphorus dichlorides. Bioorg. Med. Chem. Lett. 2005, 15, 937–943. 10.1016/j.bmcl.2004.12.050. - DOI - PubMed
    2. Bedjeguelal K.; Bienayme H.; Dumoulin A.; Poigny S.; Schmitt P.; Tam E. Discovery of protein–protein binding disruptors using multi-component condensations small molecules. Bioorg. Med. Chem. Lett. 2006, 16, 3998–4001. 10.1016/j.bmcl.2006.05.014. - DOI - PubMed
    1. Chen S.; Xia Z.; Nagai M.; Lu R.; Kostik E.; Przewloka T.; Song M.; Chimmanamada D.; James D.; Zhang S.; Jiang J.; Ono M.; Koya K.; Sun L. Novel indolizine compounds as potent inhibitors of phosphodiesterase IV (PDE4): structure–activity relationship. MedChemComm 2011, 2, 176–180. 10.1039/C0MD00215A. - DOI

LinkOut - more resources