Challenges and Breakthroughs in Selective Amide Activation

Abstract

In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural and electronic features. However, recent decades have seen the emergence of research programmes focused on the selective activation of amides under mild conditions. In the past four years, this area has continued to rapidly develop, with new advances coming in at a fast pace. Several novel activation strategies have been demonstrated as effective tools for selective amide activation, enabling transformations that are at once synthetically useful and mechanistically intriguing. This Minireview comprises recent advances in the field, highlighting new trends and breakthroughs in what could be called a new age of amide activation.

Keywords: Amide Activation; Amide Functionalisation; Electrophilic Activation; Synthetic Methods; Transition-Metal Catalysis.

Scheme 1

Illustration of amidic resonance structures.

Scheme 2

Electrophilic activation of tertiary and secondary amides with Tf₂O.

Scheme 3

A) Hydroacylation of alkenes using activated secondary amides. B) [4+2]‐Cycloaddition forming annulated nitrogen heterocycles by reaction of N‐aryl amides with alkenes to access 3,4‐dihydroquinolines 14.

Scheme 4

Enantioselective dual‐functionalisation of N‐aryl secondary amides 15 with triflic anhydride and a chiral organocatalyst.

Scheme 5

Synthesis of unusual 7‐membered fused heterocycle 21 from α‐phthalimido‐amides 20. DTBP: 2,6‐di‐tert‐butylpyridine.

Scheme 6

Synthesis of bicyclic alkoxyoxazolium salts 26 from amides 25 in the absence of base.

Scheme 7

Electrophilic amide activation in total synthesis. A) Total synthesis of (+)‐stemofoline (31) via a two‐step keto–lactam cyclisation–bromination cascade. B) Total synthesis of ilicifoline B (35) via POCl₃‐mediated amide activation.

Scheme 8

α‐Umpolung of amides with pyridine N‐oxides. A) α‐Functionalisation of amides with different nucleophiles and the proposed mechanism. B) Selected examples of fluorinated drug derivatives synthesised using the α‐fluorination of amides developed by Maulide et al. *Compounds were synthesised by reduction of the corresponding amides.

Scheme 9

Amide umpolung enables Ni‐catalysed asymmetric α‐arylation of amides 42.

Scheme 10

Synthesis of nitrogen‐containing heterocycles 48 and 49 via azide‐mediated umpolung of activated amides.

Scheme 11

Synthesis of α‐fluorinated carbonyls 52 by double electrophilic amide activation.

Scheme 12

α‐Functionalisation of amides through rearrangement process. A) α‐Allenylation and α‐allylation via Claisen rearrangement. B) α‐Deuteration of α,β‐saturated amides with [d₆]‐DMSO. C) α‐Sulfidation via sulfoxide rearrangement.

Scheme 13

β‐Functionalisation of α‐branched amides enabled by transient dehydrogenation.

Scheme 14

Selenium‐mediated α,β‐dehydrogenation of aliphatic amides.

Scheme 15

TEMPO‐mediated γ‐functionalisation of β,γ‐unsaturated amides 77.“

Scheme 16

Remote functionalisation of activated N‐alkyl amides. A) Synthesis of enamides 86 by LiHMDS‐mediated dehydrogenation of amides. B) Synthesis of spirocyclic isoindolinones 91 via amide activation and halo‐Nazarov‐type cyclisation.

Scheme 17

Organophosphorus redox‐catalysed three‐component condensation synthesis of N‐pyridyl amides 98.

Scheme 18

Dual iridium‐catalysed hydrosilylation enabling reductive functionalisation of tertiary amides.

Scheme 19

Synthesis of α‐amino 1,3,4‐oxadiazoles and related α‐amino heterodiazole via Ir‐catalysed three‐component coupling of amides with carboxylic acids and NIITP. X=O, S, NTs, NBoc, etc.

Scheme 20

Iridium‐catalysed reductive dienamine generation from lactams to access isoquinuclidines 126 via [4+2]‐cycloaddition. NP=natural product.

Scheme 21

Ir‐catalysed reductive azomethine ylide generation from amides 129, enabling access to highly functionalised pyrrolidines 131.

Scheme 22

A) Asymmetric reductive cyanation and phosphonylation of amides employing iridium with chiral thiourea. B) Asymmetric reductive alkynylation of amides by iridium/copper relay catalysis.

Scheme 23

Nickel‐catalysed transformation of twisted amides 140 into alkyl–aryl alcohols 141 via a Suzuki–Miyaura coupling/transfer hydrogenation cascade.

Scheme 24

Ni‐catalysed conversion of twisted amides 142 to the corresponding carboxylic acids 144.

Scheme 25

Peptide coupling enabled by zinc‐catalysed transamidations of tBu‐nic‐protected amides 145.

Scheme 26

Tungsten‐catalysed transamidation of tertiary alkyl amides 149 to secondary/tertiary amides 151.

Scheme 27

Controlled reduction of carboxamides to alcohols or amines by in situ generated zinc hydrides.

Scheme 28

NaH/NaI‐triggered reductive functionalisation of tertiary amides into α‐branched amines 161 and 162.

Scheme 29

Nucleophilic approach to access highly substituted cyclic nitrones 167 from N‐alkoxylactams 166 and its application in the total synthesis of cylindricine C.

Scheme 30

Iterative addition of carbon nucleophiles to N,N‐dialkyl carboxamides for the synthesis of α‐tertiary amines 174.

Scheme 31

Amide functionalisations by using gem‐diborylalkanes as pro‐nucleophiles.

Scheme 32

SmI₂/Sm‐promoted deoxygenative cross‐coupling reaction of amides with arylboronic esters.

Scheme 33

SmI₂/Sm ‐promoted deoxygenative cross‐coupling reaction of amides with polyfluoroarenes 194.