Presentation delivered at pharmaceutical society of korea conference about indolizine synthesis.

1. Dirgha Raj Joshi
PhD Candidate
Medicinal Chemistry lab,
College of Pharmacy, Yonsei University
Email: djmeropaila121@yonsei.ac.kr
Facile Access to Multi-functionalized
Indolizines Through Pyridine Construction
Supervisor: Prof. Ikyon Kim, Ph.D.
Indolizine
2022 Spring International Convention of the Pharmaceutical Society of Korea 21-22 April 2022

2. Research Topics
M. Scholtz, Chem. Ber., 1912, 45, 734
First discovery of indolizine in 1890
A. Angeli, Gazz. Chim. Iial. 1890, 26, 1793
EJMC, 2011, 46, 5237-5257
Joshi & Kim; J. Org. Chem. 2020, 85, 10994–11005
Some Biologically Active Indolizines
First synthesis of indolizine by Scholtz in 1912
Org. Biomol. Chem., 2015,13, 10986
C3 functionalization of indolizines
Angelo Angeli (1864 –1931), Italy
Famus for Angeli–Rimini reaction
Discovery, Construction & Functionalization

3. Domino [4 + 2] Annulation Access to Quinone-Indolizine Hybrids: Anticancer N-Fused Polycycles
Joshi & Kim; J. Org. Chem. 2020, 85, 10994–11005.
Joshi & Kim; J. Org. Chem. 2021, 86, 15, 10235–10248.
Michael-Aldol Double Elimination Cascade to Make Pyridines: Use of Chromone for the Synthesis of Indolizines
Inspiration from our successful annulations

4. Tetrahedron 2018, 74, 6088−6094
Joshi & Kim; Adv. Syn. Cat., 2021, 363, 23, 5330-5335
[5+1] Annulative Access to Pyridines

5. entry base (equiv) solvent temper. (°C) time (h) yield (%)
1 Cs2CO3 (2) CH3CN 120 24 39
2 K2CO3 (2) CH3CN 120 24 5
3 Na2CO3 (2) CH3CN 120 24 NR
4 Et3N (2) CH3CN 120 24 NR
5 DBU (2) CH3CN 120 24 15
6 Cs2CO3 (1.5) CH3CN 130 12 68
7 Cs2CO3 (1.5) DMSO 130 12 65
8 Cs2CO3 (1.5) 2-MeTHF 130 6 85
9 Cs2CO3 (1.5) THF 130 24 NR
10 Cs2CO3 (1.5) 2-MeTHF 130 12 68 (gm scale)
Reaction Optimization
Joshi DR & Kim I., Adv. Synth. Cat., 2021.

6. 7b (78%)
R= OMe, 7c (71%)
R= Me, 7d (79%)
7e (80%) 7f (83%) 7g (81%) 7h (83%) 7i (73%)
Reaction Scope
7j (78%) 7k (86%) 7l (73%) 7m (67%) 7n (63%) 7o (33%) 7p (78%) 7q (85%)
7r (81%) 7s (73%) 7t (75%) 7u (71%) 7v (78%)
7s
R1=OMe, R2=Cl, 7w (77%)
R1=Cl, R2=Br, 7x (72%)
Joshi DR & Kim I., Adv. Synth. Cat., 2021.

7. Conversion of 7f’ to 7f
Derivatization
Joshi DR & Kim I., Adv. Synth. Cat., 2021.

8. Control Experiments Proposed Mechanism
Joshi DR & Kim I., Adv. Synth. Cat., 2021.

9. Use of Other Methyl Ketones
Oxidation of Dihydroindolizinesa
a dry THF and added NatBuO (1.2 to 3 equiv.) at rt

10. Conclusion

12. Acknowledgement
• Prof. Ikyon Kim: Ph.D. Supervisor
• Prof. Hak Sung Kim: Master’s Supervisor
• Yonsei University: for providing Global Leader Scholarship & ARF
• Lab members
2022 Spring International Convention of the Pharmaceutical Society of Korea 21-22 April 2022