A Study on the Diazo-Transfer Reaction Using o-Nitrobenzenesulfonyl Azide

Abstract

¹⁵N-Labeled azides have a great potential as practical and effective tags for vibrational probing and hyperpolarized magnetic resonance imaging of biomolecules. They can be synthesized by reaction of primary amines with a ¹⁵N-labeled diazo-transfer reagent. TfNN¹⁵N, a γ-¹⁵N-labeled diazo-transfer reagent, was developed to prepare β-¹⁵N-labeled azides; these are vibrational probes devoid of strong spectral interference by Fermi resonance. To overcome the stability and safety problems associated with TfNN¹⁵N, there is a strong demand for the development of a novel γ-¹⁵N-labeled diazo-transfer reagent. We present a study on the diazo-transfer reaction using o-nitrobenzenesulfonyl azide (o-NsN₃). o-NsNN¹⁵N, a γ-¹⁵N-labeled diazo-transfer reagent, was newly developed and found to be better than TfNN¹⁵N with respect to its physicochemical properties and ease of synthesis. Unlike TfNN¹⁵N, however, o-NsNN¹⁵N was found to afford a mixture of β- and γ-¹⁵N-labeled azides rather than the β-¹⁵N-labeled azide alone. A mechanism for the diazo-transfer reaction of o-NsNN¹⁵N with primary amines is proposed to explain the formation of such isotopomeric mixtures.

Key words

diazo-transfer reagents - sulfonyl azides - nosyl azide - organic azides - ¹⁵N labeling - isotopomerism

• References and Notes

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• 20 o-, m-, and p-Nitrobenzenesulfonyl Azides; General ProcedureA solution of NaN₃ (1.48 g, 22.8 mmol) in H₂O (2 mL) was slowly added to a cooled (0 °C) solution of the appropriate nitrobenzenesulfonyl (nosyl) chloride 2 (5.0 g, 22.6 mmol) in THF (50 mL), and the mixture was stirred at r.t. for 3 h. The mixture was then concentrated in vacuo. The residue was dissolved in Et₂O (200 mL), washed with sat. aq NaHCO₃ (200 mL) and brine (200 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was dissolved in 1:1:1 Et₂O–CH₂Cl₂–EtOAc (30 mL) at –40 °C, and hexane (250 mL) was added. The precipitate was then collected by filtration. o-Nitrobenzenesulfonyl Azide (1a)Prepared from o-nitrobenzenesulfonyl chloride (2a; 5.0 g, 22.6 mmol) according to the general procedure as a white solid; yield: 4.92 g (96%); mp 73–74 °C; R_f = 0.25 (EtOAc–hexane, 1:5). ¹H NMR (500 MHz, CDCl₃): δ = 8.20 (dd, J = 7.8, 1.4 Hz, 1 H), 7.93 (dd, J = 7.9, 1.5 Hz, 1 H), 7.89 (td, J = 7.6, 1.5 Hz, 1 H), 7.84 (td, J = 7.6, 1.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 147.68, 135.76, 133.09, 132.50, 131.65, 125.35. HRMS (EI+): m/z [M⁺] calcd for C₆H₄N₄O₄S: 227.9953; found: 227.9956.
• 21 o-Nitrobenezenesulfonyl Hydrazide (2a′)An 80% solution of N₂H₄·H₂O (4.2 mL, 68.5 mmol) was added to a cooled (0 °C) solution of o-nitrobenzenesulfonyl chloride (2a; 3.0 g, 13.5 mmol) in THF (20 mL), and the mixture was stirred at r.t. for 1 h. The mixture then was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with sat. aq NaHCO₃ (100 mL) and brine (100 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (5 mL) at –40 °C, and hexane (100 mL) was added. The precipitate was collected by filtration to give a white solid; yield: (2.37 g, 81%); mp 100–101 °C; R_f = 0.30 (MeOH–CH₂Cl₂, 1:15).¹H NMR (500 MHz, CD₃CN): δ = 8.07 (ddd, J = 7.2, 2.0, 1.2 Hz, 1 H), 7.87 (ddd, J = 7.5, 2.3, 1.2 Hz, 1 H), 7.85 (td, J = 7.6, 1.5 Hz, 1 H), 7.82 (td, J = 7.5, 1.8 Hz, 1 H), 6.92 (br s, 1 H), 4.00 (br s, 2 H). ¹³C NMR (125 MHz, CD₃CN): δ = 149.43, 135.46, 133.41, 133.14, 130.86, 125.81. HRMS (FAB+): m/z [M + H]⁺ calcd for C₆H₈N₃O₄S: 218.0236; found: 218.0231.
• 22 γ-¹⁵N-Labeled o-Nitrobenezenesulfonyl Azide (γ-1a')1 N aq HCl (10 mL) was added to a solution of 2a′ (1.78 g, 8.22 mmol) in CH₂Cl₂ (40 mL), and the mixture was stirred at 0 °C for 5 min. A solution of Na¹⁵NO₂ (0.50 g, 7.14 mmol) in H₂O (10 mL) was then slowly added, and the resulting mixture was stirred at r.t. for a further 3 h. The mixture was then concentrated in vacuo. The residue was dissolved in Et₂O (150 mL), washed with sat. aq NaHCO₃ (150 mL) and brine (150 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by flash chromatography [silica gel, EtOAc–hexane (1:10)] to give a white solid; yield: 1.52 g (81%); mp 73–74 °C; R_f = 0.25 (EtOAc–hexane, 1:5).¹H NMR (500 MHz, CDCl₃): δ = 8.20 (dd, J = 7.8, 1.4 Hz, 1 H), 7.92 (dd, J = 7.9, 1.8 Hz, 1 H), 7.90 (td, J = 7.5, 1.2 Hz, 1 H), 7.84 (ddd, J = 7.8, 7.0, 2.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 147.62, 135.79, 133.11, 132.41, 131.62, 125.34. ¹⁵N NMR (50 MHz, CDCl₃): δ = 245.31. HRMS (EI+): m/z [M⁺] calcd for C₆H₄N₃ ¹⁵NO₄S: 228.9924; found: 228.9921.
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