Stereoselective Synthesis of Monofluoroalkyl α,β-Unsaturated Ketones From Allenyl Carbinol Esters Mediated by Gold and Selectfluor

Abstract

Allenyl carbinol ester 3 isomerizes to an E,Z mixture of the corresponding diene 2 in the presence of gold catalyst 4, but the resulting mixture yields monofluoroalkyl α,β-unsaturated ketone 1 with exclusive E selectivity and in high yields after reaction with Selectfluor.

Unique Reactivity of Fluorinated Molecules with Transition Metals

“…Based upon these observations, Hammond and coworkers employed allenyl carbinol esters 15 in the stereoselective synthesis of fluoroalkyl α,β-unsaturated ketones 17 (Scheme 14). [18] First, isomerization of the allene substrate in the presence of gold produced a diene intermediate (16), which quickly reacted with Selectfluor to exclusively give the E isomer of the corresponding fluorinated ketone 17 in high yield.…”

“…More recently, a gold-catalyzed tandem aminocyclization/electrophilic fluorination sequence has been reported by Arcadi et al for the synthesis of 3,3-difluoroand 3-fluoroindole derivatives 19 and 20 (Scheme 15). [19] Starting from o-alkynyl anilines (18) and by using an excess of Selectfluor in EtOH at room temperature, necessarily in the presence of a gold (i) or gold(iii) catalyst (e.g. Ph 3 PAuNTf 2 , AuCl, AuCl 3 or NaAuCl 4 •2H 2 O), an assorted library of C(3) difluorinated indoles 19 was prepared in good yields (Scheme 15).…”

“…In this way, the presence of fluorine in drugs has an extraordinary impact on a variety of medical applications, including anti-inflammatory, antibacterial, antitumor and antiviral agents, CNS-modulator compounds, or drugs for lowering blood cholesterol levels such as atorvastatin (Lipitor ® ), developed by Pfizer and one of the best selling drugs in the world. Furthermore, the use of 18 F-radiolabelled compounds employed in Positron Emission Tomography (PET) experiments has exponentially grown in the last few years. Therefore, the important role of the fluorine atom in medicinal chemistry is obvious, [1b,3] and it can be affirmed that fluorine chemistry will contribute significantly to the future progress in medicine.…”

Gold(I)‐Catalyzed Tandem Cycloisomerization and Fluorination of 1,3(4)‐Enyne Esters with NFSI: One‐Pot Assembly of 5‐Fluoro‐ Cyclopentenones

“…Recently, the combination of gold catalysis with fluorinating reagents has emerged as powerful strategies for the incorporation of fluorine atom into diverse molecules to deliver a number of fluorine‐containing organic complexes . For instance, Nevado's group developed a novel and efficient protocol for the preparation of α‐fluoro ketones or acetals through an alkoxylation‐fluorination of alkynes by merging gold catalysis with Selectfluor (Scheme a) .…”

“…Nevado and Gouverneur have shown that α‐fluoroenones can be synthesized from propargylic esters with Selectfluor under gold(I) catalysis, albeit the mechanism involved remains obscure (Scheme c) . A one‐pot, two‐step process for the preparation of α‐fluoroenones from allenyl carbinol esters has been realized by using gold(I) catalyst with Selectfluor (Scheme d) . Inspired by these seminal works and as part of ongoing efforts in the field of gold catalysis, we turned our attention to explore the reactivity of 1,3(4)‐enyne esters in the presence of the electrophilic fluorinating reagents such as N ‐fluorbenzensulfonimide (NFSI) (Scheme e) .…”