Lewis Acid Promoted Intramolecular Nucleophilic Heterocyclization of Unsaturated Amides for the Synthesis of 2-Oxazolines and Their Applications in Imaging of Living Cells

doi:10.6023/cjoc202201036

Abstract

2-Oxazolines and their derivatives are important scaffolds present in the fields of organic synthesis, material science and biomedicine. An efficient, mild and metal-free process to synthesize 2-oxazoline derivatives was reported. Various 2-oxazoline derivatives were synthesized through the Lewis acid-mediated intramolecularly nucleophilic heterocyclization of unsaturated amides in high to excellent yields (80%~94% isolated yields). Besides, the experiments of imaging of living cells were conducted to verify the proper fluorescence properties of the 2-oxazoline derivative. The results indicated that the probe had good cellular compatibility, as well as the potential to track spatial dynamics in living cells.

Key words: Lewis acid, gheterocyclization, 2-oxazoline, cell imaging

Cite this article

Xuerong Chen, Liang Qi, Jinpei Huang, Weiwei Zhu, Yifeng Zhou. Lewis Acid Promoted Intramolecular Nucleophilic Heterocyclization of Unsaturated Amides for the Synthesis of 2-Oxazolines and Their Applications in Imaging of Living Cells[J]. Chinese Journal of Organic Chemistry, 2022, 42(7): 2155-2163.

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Fig. & Tab. 7

Scheme 1. Application examples and synthesis of 2-oxazolines

Entry	LA^b	Solvent	Temperature/℃	Yield^c/%
1	BF₃•Et₂O	DCM	0	12
2	BF₃•Et₂O	DCM	25	65
3	TFA	DCM	25	0
4	AcOH	DCM	25	0
5	MsOH	DCM	25	0
6	FeCl₃	DCM	25	0
7	ZnCl₂	DCM	25	0
8	MeOTf	DCM	25	0
9	TMSOTf	DCM	25	85
10	TMSOTf	MeCN	25	82
11	TMSOTf	C₆H₅Cl	25	79
12	TMSOTf	CHCl₃	25	77
13	TMSOTf	DCE	25	94
14	TMSOTf	DMF	25	Trace
15^d	TMSOTf	DCE	25	Trace

Table 1. Optimization of the reaction conditionsa

Table 2. Substrat scope of the TMSOTf promoted heterocyclizationa

Scheme 2. Possible reaction mechanism

Figure 3. Confocal microscope images of Hela cells incubated with 11b (20 μmol/L) for different incubation times (λex=405 nm, λem=470±20 nm. Scale bar=20 μm)

Figure 4. Co-localization of 11b (20 μmol/L, 1 h) with BODIPY 493/503 (100 nmol/L, 30 min), LTR (100 nmol/L, 30 min) and MTR (100 nmol/L, 30 min) in HeLa cells by confocal microscopy images Scale bar: 20 μm. λex/em=405/(470±20) nm for 11b, λex/em=488/(510±10) nm for BODIPY 493/503, λex/em=561/(580±10) nm for MTR and LTR.

Figure 4. Z-Stack scans images of Hela cells incubated with 11b (20 μmol/L) for 1 h (λex=405 nm, λem=470±20 nm. Scale bar=20 μm)

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