Ethyl Dibromofluoroacetate (EDBFA)

Cátia V. Almeida Santos was born in Lisbon, Portugal. She received her degree in biochemistry from the Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa in 2013. Currently, she is carrying out research under the supervision of Professor M. Manuel B. Marques at the Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa on the synthesis of biologically active glycopeptides.

Introduction

Over the last decades, fluorinated organic compounds have increasingly received great attention by the scientific community; in several scientific fields, from material science to medicine. Today, approximately 30% of all agrochemicals and 20% of all pharmaceuticals contain fluorine.[1] [2] The unique properties of fluorinated compounds are due to the high electronegativity of fluorine, the small size of fluorine, and the significant electrostatic character of the C–F bond.[3] The presence of a fluorine atom in organic compounds imparts several properties (basicity, lipophilicity, and metabolic stability) which in some cases enhance the drug-like properties of the molecule.[4]

A useful and commercially available reagent for fluorination of organic compounds is ethyl dibromofluoroacetate [EDBFA (1), Figure [1]].[5]

Figure 1 Ethyl dibromofluoroacetate (EDBFA)

Fluoroacetate 1 is a solid with a molecular weight of 263.89 g/mol, a boiling point of 173 °C, and a density of 1.92 g/cm³.[5] Derivatives of EDBFA such as compounds 2–6 (Scheme [1]) are also efficient reagents.[6] Replacement of one bromine atom in 1 by an azide generates a stereocenter, affording ethyl 2-azido-2-bromo-2-fluoroacetate (2). A two-step strategy is used to convert the ester moiety into the corresponding nitrile to give the 2,2-dibromo-2-fluoroacetonitrile (3).

Scheme 1 Synthesis of EDBFA derivatives

Using lithium borohydride as the reducing agent and trimethylborate, the ester moiety of 1 can be converted into an alcohol to give 2-azido-2-bromo-2-fluoroethan-1-ol (4).[6] [7] It can also be changed into a tertiary amide in the presence of dimethylaluminium chloride, affording 2-azido-2-bromo-N,N-diethyl-2-fluoroacetamide (5) or be transformed in the corresponding acyl chloride, via a three-step procedure, to afford 2-azido-2-bromo-2-fluoroacetyl chloride (6).

Abstracts

(A) The Reformatsky-type reaction of 1 with (E)-N-benzyl-1-phenylmethanimine (7), mediated by diethylzinc, was performed to achieve a chemo- and diastereoselective synthesis of the α-bromo-α-fluoro-β-lactam 8 in 76% yield as a single diastereomer, with syn configuration between the hydrogen and fluorine atom.[8]
(B) 1 can be used for the formation of fluorinated epoxides. The reaction of 1 with a ketone in the presence of diethylzinc and N,N-dimethylaminoethanol gives access to the corresponding fluorinated glycidic ester. The authors have improved a previously reported procedure by replacing triphenylphosphine with N,N-dimethylaminoethoxide (prepared in situ from the reaction of Et2Zn with N,N-dimethylaminoethanol). The compounds are obtained with high purity after a very simple isolation procedure.[9] [10]
(C) A general and versatile approach for the formation of monofluorinated cyclopropanes using 1 was reported.[11] This procedure consists of a Michael addition of zinc enolates, generated from 1 with Zn and LiCl, to electron-deficient alkenes followed by nucleophilic cyclization. The most reproducible procedure involved previous treatment of Zn and LiCl with 2 mol% DMSO and 2 mol% TMSCl in THF. This also allowed the preparation of spiro-oxindoles fluorinated in a nonaromatic position.
(D) The addition of 1 to a carbonyl derivative mediated by Et2Zn occurs by two different pathways depending on the nature of the carbonyl compound. This strategy led to the syntheses of α-fluoroacrylates via a one-pot stereoselective approach. When aldehydes are used, the reaction follows an E2-type mechanism, whereas with ketones the reaction follows an E1cB-type mechanism. This strategy tolerates various functional groups including esters, nitriles, and protected alcohols. Aldehydes were converted into α-fluoroacrylates in pure Z form. However, in most cases, the α-bromo-α-­fluoro-β-hydroxy esters afforded the syn isomer selectively. Concerning ketones, good stereoselectivity could only be afforded for unsymmetrical ketones possessing one hindered group.[12]
(E) EDBFA derivative 4 was used in the preparation of dibromofluoromethylcarbinyl esters 12 from carbamates. Compound 4 was prepared by reduction of 1 with LiBH4 in the presence of trimethyl­borate.[6] [7] The dibromofluoromethylcarbinyl esters 11 are useful for the preparation of 1-fluro-1-alkenyl carbamates 12 via a [2,3]-sigmatropic rearrangement mediated by CrCl2 and Mn.[13]

• References

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• 5 Data taken from the EUROPE Catalog, TCI Fine Chemicals 2012–2013.
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