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Expanded Access to Fluoroformamidines via a Modular Synthetic Pathway

James A. Vogel, Kirya F. Miller, Eunjeong Shin, Jenna M. Krussman, Patrick R. Melvin*

*Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, United States, Email: prmelvinbrynmawr.edu

J. A. Vogel, K. F. Miller, E. Shin, J. M. Krussman, P. R. Melvin, Org. Lett., 2024, 26, 1277-1281.

DOI: 10.1021/acs.orglett.4c00131


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Abstract

A rearrangement of in situ-generated amidoximes enables a practical and modular synthesis of fluoroformamidines. High yields in just 60 s at room temperature highlight the efficiency of this protocol. Furthermore, fluoroformamidines proved to be useful intermediates in the synthesis of diverse ureas and carbamimidates.


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proposed mechanism



Formation of fluoroformamidines from acid chloride oximes

To an 8 mL vial equipped with a flea stir bar, acid chloride oxime (0.20 mmol) and NEt3 (61.0 mg, 0.60 mmol) were added along with acetonitrile (0.5 mL). Morpholine (17.4 mg, 0.20 mmol) dissolved in acetonitrile (0.25 mL) was added at room temperature and stirred for 30 seconds before SIF (160 mg, 0.40 mmol) dissolved in acetonitrile (0.25 mL) completed the additions. The reaction was stirred for 60 seconds at room temperature at which time the acetonitrile was removed under reduced pressure. The crude reaction mixture was then purified via silica gel chromatography (12 g silica gel column), using DCM and ethyl acetate as the eluent (0% → 40% gradient).

Conversion of acid chloride oximes to carbamimidate derivatives via fluoroformamidines

To an 8 mL vial equipped with a flea stir bar, acid chloride oxime (0.20 mmol) and NEt3 (61.0 mg, 0.60 mmol) were added along with acetonitrile (0.5 mL). Amine (0.20 mmol) dissolved in acetonitrile (0.25 mL) was added at room temperature and stirred for 30 seconds before SIF (160 mg, 0.40 mmol) dissolved in acetonitrile (0.25 mL) completed the additions. The reaction was stirred for 60 seconds at room temperature at which time phenol (1.0 mmol) and NEt3 (101 mg, 1.0 mmol) were added in acetonitrile (0.5 mL) and the reaction was allowed to stir for 24 hours at 80°C using a hot plate + PIE-BLOCK. Following the completion of the reaction, the acetonitrile was removed under reduced pressure and the crude mixture was then purified by silica gel chromatography (12 gram silica gel column) using DCM / ethyl acetate as the eluent (0 → 100% gradient).


Key Words

amidines, isoureas, fluorination


ID: J54-Y2024