1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities

Abstract

In synthetic organic chemistry, there are very useful basic compounds known as building blocks. One of the main reactions wherein they are applied for the synthesis of complex molecules is the Diels-Alder cycloaddition. This reaction is between a diene and a dienophile. Among the most important dienes are the cyclic dienes, as they facilitate the reaction. This review considers the synthesis and reactivity of one of these dienes with special characteristics-it is cyclic and has an electron withdrawing group. This building block has been used for the synthesis of biologically active compounds and is present in natural compounds with interesting properties.

Keywords: Diels–Alder; aldehydes; chiral compounds; dienes; synthesis.

Figure 1

Natural and synthetic compounds with 1,3-cyclohexadien-1-al scaffold.

Figure 2

Summary of methodologies for the obtention of 1,3-cyclohexadien-1-als. The corresponding bibliography is shown in blue numbers.

Scheme 1

Semisynthesis of safranal 2.

Scheme 2

Synthesis of safranal 2 from α-cyclocitronitrile.

Scheme 3

Transformation of botrydial 14 into botrydienal 6 by reaction with Ag₂CO₃.

Scheme 4

Isomerization of dienal 15.

Scheme 5

Synthesis of terephthalic derivatives from biomass.

Scheme 6

Synthesis of cyclohexandienals under Vilsmeier–Haack reaction conditions.

Scheme 7

Carvone 35 formylation under Vilsmeier–Haack conditions.

Scheme 8

Formylation reaction in the synthetic preparation of cyclohexadienal motif.

Scheme 9

Self-dimerization of glutaraldehyde 43.

Scheme 10

Self-condensation of α,β-aldehydes in the formation of 1,3-cyclohexadien-1-al units.

Scheme 11

Self-condensation of senecialdehyde 47 in the formation of 1,3-cyclohexadien-1-al 50.

Scheme 12

Cross-condensation of unsaturated aldehydes in the formation of 1,3-cyclohexadien-1-als.

Scheme 13

Self-condensation of α,β-unsaturated aldehyde 46 in the formation of 1,3-cyclohexadien-1-al 49.

Scheme 14

Michael and Horner–Wadsworth–Emmons reactions in the synthesis of cyclohexadienal 50.

Scheme 15

Michael and Horner–Wadsworth–Emmons reactions in the synthesis of cyclohexadienals.

Scheme 15

Michael and Horner–Wadsworth–Emmons reactions in the synthesis of cyclohexadienals.

Scheme 16

Diels–Alder reactions towards the synthesis of 1,3-cyclohexadien-1-al scaffold.

Scheme 17

Diels–Alder reaction towards the synthesis of 1,3-cyclohexadien-1-al scaffold.

Scheme 18

Diels–Alder reaction towards the synthesis of 1,3-cyclohexadien-1-al scaffold.

Scheme 19

Diels–Alder reaction towards the synthesis of hexafluorinated safranal 97.

Scheme 20

Diels–Alder reaction of vinamidium salts and unsaturated aldehydes.

Scheme 21

Synthesis and thermal cyclization of hexatrienes 106 and 109; CuTC = copper(I) thiophene-2-carboxylate.

Scheme 22

Ruthenium catalyzed electrocyclization in the preparation of 1,3-cyclohexadienal scaffold.

Scheme 23

Employment of organoaluminium reagent in the synthesis of cyclohexadienal 1.

Scheme 24

Cr(CO)₃ complex-mediated dearomatization in the synthesis of cyclohexadienals.

Scheme 25

Cr(CO)₃ complex-mediated dearomatization in the presence of chiral ligands.

Scheme 26

Selection of Cr(CO)₃ complexes used in dearomatization reactions for the preparation of cyclohexadienals.

Scheme 27

Cr(CO)₃ complex-mediated dearomatization in the synthesis of cyclohexadienals towards acetoxytubipofuran.

Scheme 28

Organocatalyzed synthesis of 1,3-cyclohexadien-1-als from citral 51.

Scheme 29

Organocatalytic self-condensation of α,β-unsaturated aldehydes towards 1,3-cyclohexadien-1-al compounds.

Scheme 30

Organocatalyst-mediated cycloaddition of α,β-unsaturated aldehydes towards 1,3-cyclohexadien-1-al compounds.

Scheme 31

Examples of cyclohexadienals obtained in L-proline-mediated reaction of α,β-unsaturated aldehydes.

Scheme 32

Intramolecular organocatalytic formation of cyclohexadienal unit.

Scheme 33

Organocatalyst-mediated cycloaddition for the synthesis of cyclohexadienal core.

Scheme 34

Organocatalytic-mediated synthesis of chiral 1,3-cyclohexadienals.

Scheme 35

Organocatalytic-mediated synthesis of chiral 1,3-cyclohexadienal 179.

Scheme 36

Organocatalytic-mediated synthesis of cyclodienal and subsequent reaction with conjugated aldehyde 181.

Scheme 37

Synthesis of cyclohexadienal compounds and subsequent cycloaddition reaction.

Scheme 38

Dihydroxilation of 1,3-cyclohexadien-1-carboxaldehyde in the total synthesis of fumagillol 190.

Scheme 39

Dihydroxilation of cyclohexadienal 150 in the total synthesis of (+)-palitantin 193.

Scheme 40

Hydrogenation of hexafluorinated safranal 97.

Scheme 41

Oxyallyl cycloaddition reaction with cyclohexadienal.

Scheme 42

Formation of tricarbonyl iron complex of 1,3-cyclohexadiene-1-carboxaldehyde 1.

Scheme 43

Aromatization reaction of cyclohexadienals.

Scheme 44

Aromatization reaction of phenyl-substituted cyclohexadienals.

Scheme 45

Organocatalytic synthesis of cyclohexadienals/oxidation reaction in the synthesis of aromatic aldehydes.

Scheme 46

Organocatalytic synthesis of cyclohexadienals/aromatization reaction in the synthesis of pentasubstituted aromatic compounds.

Scheme 47

Oxidation of 1,3-cyclohexadien-1-carboxaldehyde to carboxylic acid 203.

Scheme 48

Reduction of safranal 2 to alcohol 206.

Scheme 49

Reduction of natural aldehydes 61 and 63 to the corresponding alcohols.

Scheme 50

Reduction of the aldehyde moiety in the 1,3-cyclohexadien-1-al core in the total synthesis of acetoxytubipofuran.

Scheme 51

Reduction of the cyclohexadienal core in the synthesis of (−)-drimenol.

Scheme 52

Horner–Wadsworth–Emmons reaction of safranal.

Scheme 53

Reaction of safranal with a Grignard reagent.

Scheme 54

Reaction of cyclohexadiene carboxaldehyde unit with a Grignard reagent.

Scheme 55

Reaction of safranal 2 with an organolithium reagent.

Scheme 56

Intramolecular cyclization in the preparation of diazecine derivatives.

Scheme 57

Intramolecular macrocyclization in the preparation of eunicellane skeletons.

Scheme 58

Intramolecular macrocyclization in cyclohexadienal derivative.

Scheme 59

Organocuprate addition in cyclohexadienal derivative 74.

Scheme 60

Inverse electron demand hetero-Diels–Alder reaction of cyclohexadienal derivative 222.

Scheme 61

Cycloaddition reaction of cyclohexadienal derivative 222.

Figure 3

Heterodimeric and dimeric 1,3-cyclohexadien-1-als (226–237) and examples biologically active.