Synergistic Catalysis: A Powerful Synthetic Strategy for New Reaction Development

Abstract

Synergistic catalysis is a synthetic strategy wherein both the nucleophile and the electrophile are simultaneously activated by two separate and distinct catalysts to afford a single chemical transformation. This powerful catalysis strategy leads to several benefits, specifically synergistic catalysis can (i) introduce new, previously unattainable chemical transformations, (ii) improve the efficiency of existing transformations, and (iii) create or improve catalytic enantioselectivity where stereocontrol was previously absent or challenging. This perspective aims to highlight these benefits using many of the successful examples of synergistic catalysis found in the literature.

Fig. 1

The concept of synergistic catalysis.

Fig. 2

Classification of catalytic systems involving two catalysts.

Fig. 3

Synergistic catalysis in dihydrofolate reductase.

Fig. 4

The total number of publications describing asymmetric synergistic catalysis from January 1993 to May 2011.

Fig. 5

Fig 4 Examples of Sonogashira substrates that undergo alkynylation using synergistic palladium- and copper-catalysis.

Scheme 1

Rhodium- and palladium-catalyzed enantioselective allylic alkylation of α-cyano carbonyls.

Scheme 2

Mechanism of the rhodium- and palladium-catalyzed allylic alkylation of α-cyano carbonyls.

Scheme 3

Córdova’s direct α-allylation of unactivated aldehydes and ketones via enamine and palladium π-allyl intermediates.

Scheme 4

Mechanism of the enantioselective α-allylation of aldehydes and ketones via enamine and palladium π-allyl intermediates.

Scheme 5

An enantioselective α-allylation of aldehydes and ketones via enamine and palladium π-allyl intermediates.

Scheme 6

Takemoto’s α-allylic alkylation of glycine imino esters.

Scheme 7

α-Allylic alkylation of glycine imino esters via phase transfer and palladium catalysis.

Scheme 8

Trost’s palladium- and vanadium-catalyzed synthesis of α-allyl-α,β-unsaturated ketones.

Scheme 9

Mechanism of the palladium- and vanadium-catalyzed α-allyl enone formation.

Scheme 10

General mechanism of enamine catalysis with metal-bound electrophiles to generate α-substituted carbonyls.

Scheme 11

Wu’s synthesis of 1,2-dihydroisoquinoline derivatives.

Scheme 12

MacMillan’s organocatalytic α-trifluoromethylation of aldehydes using Togni’s reagent and CuCl.

Scheme 13

Nishibayashi’s enantioselective α-propargylation of aldehydes via enamine and transition metal catalysis.

Scheme 14

Nishibayashi’s enantioselective α-propargylation of aldehydes using internal alkynes via enamine and indium catalysis.

Scheme 15

MacMillan’s copper-catalyzed enantioselective α-oxyamination of aldehydes.

Scheme 16

Organocatalytic α-arylation of aldehydes via the merger of enamine and copper catalysis.

Scheme 17

The reductive cleavage of electron-poor alkyl bromides for use in photoredox organocatalysis.

Scheme 18

General mechanism for the photoredox enantioselective α-alkylation of aldehydes.

Scheme 19

Examples of photoredox organocatalysis reported by MacMillan and coworkers.

Scheme 20

Mechanism of the photoredox organocatalytic α-benzylation of aldehydes.

Scheme 21

Zeitler’s photoredox protocol using organic photocatalysts.

Scheme 22

Oxidative coupling reactions of cyclic tertiary amines and methyl ketones reported by Klussmann and Rueping.

Scheme 23

An enantioselective three-component domino reaction via synergistic hydrogen-bond and enamine catalysis.

Scheme 24

Córdova’s catalytic enantioselective silyl conjugate addition to α,β-unsaturated aldehydes via copper and iminium catalysis.

Scheme 25

Direct γ-benzylic alkylation of α-branched enals via the merger of chiral dienamine and Brønsted acid catalysis.

Scheme 26

Formation of tetrahydroxanthenones via organocatalytic enantioselective oxa-Michael–Mannich reaction.

Scheme 27

Jacobsen’s conjugate cyanation of unsaturated imides.

Scheme 28

General mechanism for the addition of metal acetylides to Brønsted acid activated imines.

Scheme 29

Asymmetric synthesis of propargylic amines via the merger of transition metal catalysis with Brønsted acid catalysis.

Scheme 30

Li’s ruthenium- and copper-catalyzed synthesis of propargyl alcohols and amines.

Scheme 31

Beller’s catalytic asymmetric hydrogenation of imines using a simple achiral iron catalyst and a chiral Brønsted acid catalyst.

Scheme 32

The reductive amination of methyl ketones catalyzed by a chiral iridium complex and a chiral Brønsted acid.

Scheme 33

The three-component coupling of diazoacetates, alcohols, and imines catalyzed by chiral Brønsted acids and Rh₂(OAc)₄.

Scheme 34

Mechanism of the three-component coupling of diazoacetates, alcohols, and imines via rhodium- and Brønsted acid catalysis.

Scheme 35

The four-component coupling of diazoacetates with alcohol, aldehydes, and amines to generate β-amino-α-hydroxyesters.

Scheme 36

The three-component coupling of diazoacetates, carbamates, and imines using a chiral Brønsted acid and Rh₂(OAc)₄.

Scheme 37

Enantioselective aza-Henry reaction via chiral organic and Lewis acid catalysis.

Scheme 38

Corey’s enantioselective cyanation of aldehydes using TMSCN with Lewis acid and Lewis base catalysts.

Scheme 39

The enantioselective cyanation of ketones catalyzed by metal-salen complexes and dimethylphenylamine N-oxide.

Scheme 40

Proposed transition states for the Lewis acid and Lewis base catalyzed cyanation of ketones.

Scheme 41

The asymmetric synthesis of β-lactams catalyzed by benzoylquinine and In(OTf)₃.

Scheme 42

The asymmetric synthesis of (A) β-lactones and (B) β-sultones using cinchona alkaloid and metal Lewis acid catalysts.

Scheme 43

Scheidt’s γ-lactam formation via a [3 + 2] annulation catalyzed by an N-heterocyclic carbene and a Lewis acid.

Scheme 44

The Sonogashira coupling reaction first disclosed in 1975 by Sonogashira, Tohda, and Hagihara.

Scheme 45

Palladium- and copper-catalyzed Stille coupling reaction.

Scheme 46

Palladium- and copper-catalyzed Stille coupling reactions.

Scheme 47

Synergistic palladium-catalyzed cyanation of aryl halides.

Scheme 48

Direct dehydrative cross-coupling of tautomerizable heterocycles and alkynes via palladium and copper catalysis.

Scheme 49

Three-component coupling of benzyne, allylic epoxides, and terminal acetylenes.

Scheme 50

Palladium- and ruthenium-catalyzed coupling of 2-pyridylmethyl formate with aryl and vinyl halides.

Scheme 51

Palladium- and ruthenium-catalyzed coupling of aryl formates with aryl halides.