A review of new developments in the Friedel-Crafts alkylation - From green chemistry to asymmetric catalysis

Abstract

The development of efficient Friedel-Crafts alkylations of arenes and heteroarenes using only catalytic amounts of a Lewis acid has gained much attention over the last decade. The new catalytic approaches described in this review are favoured over classical Friedel-Crafts conditions as benzyl-, propargyl- and allyl alcohols, or styrenes, can be used instead of toxic benzyl halides. Additionally, only low catalyst loadings are needed to provide a wide range of products. Following a short introduction about the origin and classical definition of the Friedel-Crafts reaction, the review will describe the different environmentally benign substrates which can be applied today as an approach towards greener processes. Additionally, the first diastereoselective and enantioselective Friedel-Crafts-type alkylations will be highlighted.

Keywords: Friedel–Crafts alkylation; Lewis-acid catalysis; allyl alcohols; arene; asymmetric Friedel–Crafts reaction; benzyl alcohols; green chemistry; hydroalkylation; hydroarylation; propargyl alcohols.

Scheme 1

AlCl₃-mediated reaction between amyl chloride and benzene as developed by Friedel and Crafts.

Figure 1

Most often used metal salts for catalytic FC alkylations and hydroarylations of arenes.

Figure 2

1,1-diarylalkanes with biological activity.

Scheme 2

Alkylating reagents and side products produced.

Scheme 3

Initially reported TeCl₄-mediated FC alkylation of 1-penylethanol with toluene.

Scheme 4

Sc(OTf)₃-catalyzed FC benzylation of arenes.

Scheme 5

Reductive FC alkylation of arenes with arenecarbaldehydes.

Scheme 6

Iron(III)-catalyzed FC benzylation of arenes and heteroarenes.

Scheme 7

A gold(III)-catalyzed route to beclobrate.

Scheme 8

Catalytic FC-type alkylations of 1,3-dicarbonyl compounds.

Scheme 9

Iron(III)-catalyzed synthesis of phenprocoumon.

Scheme 10

Bi(OTf)₃-catalyzed FC alkylation of benzyl alcohols developed by Rueping et al.

Scheme 11

(A) Bi(OTf)₃-catalyzed intramolecular FC alkylation as an efficient route to substituted fulvenes. (B) Nanostructured MoO₃ mediated intramolecular FC alkylation.

Scheme 12

FC-type glycosylation of 1,2-dimethylindole and trimethoxybenzene.

Scheme 13

FC alkylation with highly reactive ferrocenyl- and benzyl alcohols. The reaction proceeds even without Lewis acids just “on water”.

Scheme 14

Reductive FC alkylation of arenes with benzaldehyde and acetophenone catalyzed by the Ir-carbene complex 33.

Scheme 15

Formal synthesis of 1,1-diarylalkanes from benzyl alcohols and styrenes.

Scheme 16

(A) Mo-catalyzed hydroarylation of styrenes and cyclohexenes. (B) Hydroalkylation–cyclization cascade leading to 1,1-diarylalkane 38 from the linear precursor citral (37).

Scheme 17

Bi(III)-catalyzed hydroarylation of styrenes with arenes and heteroarenes.

Scheme 18

BiCl₃-catalyzed ene/FC alkylation reaction cascade – A fast access to highly arylated dihydroindenes.

Scheme 19

Au(I)/Ag(I)-catalyzed hydroarylation of indoles with styrenes, aliphatic and cyclic alkenes.

Scheme 20

First transition-metal-catalyzed ortho-hydroarylation developed by Beller et al.

Scheme 21

(A) Ti(IV)-mediated rearrangement of an N-benzylated aniline to the corresponding ortho-alkylated aniline. (B) ortho-Arylation of anilines with styrenes in the presence of TiCl₄.

Scheme 22

Dibenzylation of aniline gives potentially useful amine-based ligands in a one-step procedure.

Scheme 23

FC-type alkylations with allyl alcohols as alkylating reagents – linear vs. branched product formation.

Scheme 24

(A) First catalytic FC allylation and cinnamylation using allyl alcohols and its derivatives. (B) Efficient Mo-catalyzed synthesis of methyleugenol.

Scheme 25

FC allylation/cyclization reaction yielding substituted chromanes.

Scheme 26

Synthesis of (all-rac)-α-tocopherol utilizing Lewis- and strong Brønsted-acids.

Scheme 27

Au(III)-catalyzed cinnamylation of arenes.

Scheme 28

“Exhaustive” allylation of benzene-1,3,5-triol.

Scheme 29

Palladium-catalyzed allylation of indole.

Scheme 30

Pd-catalyzed synthesis of pyrroloindoles from L-tryptophane.

Scheme 31

Ru(IV)-catalyzed allylation of indole and pyrroles with unique regioselectivity.

Scheme 32

Silver(I)-catalyzed intramolecular FC-type allylation of arenes and heteroarenes.

Scheme 33

FC-type alkylations of arenes using propargyl alcohols.

Scheme 34

(A) Propargylation of arenes with stoichiometric amounts of the Ru-allenylidene complex 86. (B) First catalytic propargylation of (hetero)arenes using a cationic Ru-complex.

Scheme 35

Diruthenium-catalyzed formation of chromenes and 1H-naphtho[2,1-b]pyrans.

Scheme 36

Rhenium(V)-catalyzed FC propargylations as a first step in the total synthesis of podophyllotoxin, mimosifoliol and O-methyldetrol.

Scheme 37

Scandium-catalyzed arylation of 3-sulfanyl- and 3-selanylpropargyl alcohols.

Scheme 38

Synthesis of 1,3-diarylpropynes via direct coupling of propargyl trichloracetimidates and arenes.

Scheme 39

Diastereoselective substitutions of benzyl alcohols.

Scheme 40

(A) First diastereoselective FC alkylations developed by Bach et al. (B) anti-Selective FC alkylation of α-phenyl substituted benzyl alcohols.

Scheme 41

Diastereoselective AuCl₃-catalyzed FC alkylation.

Scheme 42

Bi(OTf)₃-catalyzed alkylation of α-chiral benzyl acetates with silyl enol ethers.

Scheme 43

Bi(OTf)₃-catalyzed diastereoselective substitution of propargyl acetates.

Scheme 44

Nucelophilic substitution of enantioenriched ferrocenyl alcohols.

Scheme 45

First catalytic enantioselective propargylation of arenes.