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. 2024 Mar 8;29(6):1221.
doi: 10.3390/molecules29061221.

Stereoselective [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with Azaoxyallyl Cations to Access Functionalized 1,4-Benzodiazepin-3-ones

Yoseop Kim  1 , Sung-Gon Kim  1
Affiliations

Stereoselective [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with Azaoxyallyl Cations to Access Functionalized 1,4-Benzodiazepin-3-ones

Yoseop Kim et al. Molecules. .

Abstract

The 1,4-benzodiazepine structural framework is a fascinating element commonly found in biologically active and pharmaceutically relevant compounds. A highly efficient method for synthesizing 1,4-benzodiazepin-3-ones is described, involving a [4+3]-cycloaddition reaction between 2-amino-β-nitrostyrenes and α-bromohydroxamate, with Cs2CO3 used as a base. This process yielded the desired 1,4-benzodiazepines in good yields. Furthermore, an organocatalytic asymmetric [4+3]-cycloaddition was successfully accomplished using a bifunctional squaramide-based catalyst. This approach enabled the enantioselective synthesis of chiral 1,4-benzodiazepines with commendable yields and moderate enantioselectivities, reaching up to 80% yield and 72% ee.

Keywords: 1,4-benzodiazepine; [4+3]-cycloaddition; asymmetric catalysis; azaoxyallyl cation; organocatalysis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Biologically active compounds containing the 1,4-benzodiazepione skeleton.
Scheme 1
Scheme 1
Synthetic of 1,4-benzodiazepiones using [4+3]-cycloaddition with azaoxyallyl cations.
Scheme 2
Scheme 2
Substrate scope for the [4+3]-cycloaddition of 2-amino-β-nitrostyrenes with α-bromohydroxamates a,b. a Standard reaction conditions: 1a (0.20 mmol), 2 (0.30 mmol), Cs2CO3 (0.40 mmol), and CH2Cl2/HFIP (1:1, 1.0 mL), stirred at rt for 1 h. b Isolated yield after chromatographic purification.
Figure 2
Figure 2
Chiral squaramide-based and thiourea-based catalysts.
Scheme 3
Scheme 3
Substrate scope for asymmetric [4+3]-cycloaddition of 2-amino-β-nitrostyrenes with α-bromohydroxamates a,b,c. a Standard reaction conditions: 1 (0.10 mmol), 2 (0.30 mmol), Na2CO3 (0.25 mmol]), HFIP (0.12 mmol]), III (0.010 mmol) and CH2C12 (1.0 mL), stirred at rt. b Isolated yield after chromatographic purification. c ee was determined by chiral HPLC. d Trace amounts of the product were detected.
Scheme 4
Scheme 4
One-mmol scale synthesis.
Scheme 5
Scheme 5
Synthetic transformations.
Figure 3
Figure 3
The Plausible transition state of the reaction.
See this image and copyright information in PMC

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