Decarbethoxylative Arylation Employing Arynes: A Metal-Free Pathway to Arylfluoroamides

Abstract

An efficient, metal-free decarbethoxylative arylation protocol for the synthesis of α-aryl-α-fluoroamides from fluoromalonamates, under ambient reaction conditions using aryne as an electrophilic arylating agent, is reported. This decarbethoxylative arylation proceeds under mild conditions and provides a practical and effective entry to a wide range of α-aryl-α-fluoroacetamides. Interestingly, the use of the tert-butyl ester of fluoromalonamate prevented the otherwise rapid decarboxylation step, affording the arylated fluoromalonamate in moderate yield.

Structure of 2-chloro-N-(p-tolyl)propanamide

“…A search of the Cambridge Structural Database (CSD version 5.39, February 2018 update; Groom et al, 2016) for similar systems (R-PhNHCOCH-, where R = H, methyl, halogen) yielded several similar substituted phenylacetamides: CLACTN (Subramanian, 1966), CLACTN01 (Gowda et al, 2007a), CLACTN02 (Naumov et al, 2007), CLACTN03 [Coles (né e Huth) et al, 2008], CEXPOK (Banks et al, 1999), FOWYIA (Gowda et al, 2009), IFALIK (Frohberg et al, 2002), IQOHOL (Gowda et al, 2003), JODQEZ (Si-shun Kang et al, 2008), NIYYEB (Pathak et al, 2014), NUWQUT (Hursthouse et al, 2009), NUZBUF (Pal et al, 1998), NUZBUF01 (Gowda et al, 2001), RIYWIG (Gowda et al, 2008), SALYIN (Chekhlov et al, 1987), WINSUI (Gowda et al, 2007b), XEKNEJ (Gupta et al, 2017), XICMAY (Gowda et al, 2007c), XIHMIK and XIHMOQ (Gowda et al, 2001) and XIQNIV (Staples & Vidnovio, 2007).…”

Synthesis of α‐Fluoroamides with a C–F Quaternary Stereogenic Center by Electrophilic Fluorination: One‐Pot Four‐Component Strategy

“…Recently, Jianwei and co‐workers pioneered the one‐pot synthesis of α‐fluoroamides from α‐chloro aldehydes using NHC ( N ‐heterocyclic carbenes) as a catalytic system . Later on, several research groups developed the methods for the synthesis of α‐fluoroamides starting from diverse substrates with different reaction conditions such as Abigail disclosed the synthesis of α‐fluoroamides starting from diazo compound in presence of copper‐catalysis, whereas Kishor and co‐workers reported the preparation of α‐fluoroamides by the reaction of fluoromalonamates with different arynes . In our case, we have developed a method to synthesize α‐fluoroamides in a one‐pot four‐component strategy using NFSI as an electrophilic fluorinating reagent.…”

“…However, amide or peptide bond formation is an active area in organic chemistry due to their effective role in biology and drug discovery,, the selective incorporation of fluorine into α‐position of amide functional group in a molecule may additionally gains special interest in medicinal chemistry (Figure ) . The aforementioned research work reveals that great advances were done in the synthesis of α‐fluoroamide skeleton containing molecules (Figure ) . Recently, Jianwei and co‐workers pioneered the one‐pot synthesis of α‐fluoroamides from α‐chloro aldehydes using NHC ( N ‐heterocyclic carbenes) as a catalytic system .…”

Superseding Substrate Control with Catalyst Control to Improve Regioselectivity in Aryne Annulations

“…[1][2][3][4][5][6][7][8][9][10] One challenge is the use of unsymmetrically substituted arynes as multiple regioisomeric products are possible. 6,[11][12][13][14][15][16][17][18][19][20] As stated by Li and coworkers in a recent review on arynes, "Regioselectivity is a fundamental issue in aryne chemis-try…the diminished reaction efficiency attributed by the formation of an unwanted regioisomer in an aryne transformation will severely damage its synthetic application." 6 To illustrate this limitation, in a report by Yoshida and coworkers for the synthesis of phenoxathiins, a 54:46 ratio of regioisomers was observed when using a Kobayashi precursor to generate an omethyl aryne (Figure 1a).…”