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Review
. 2025 May 28:21:1031-1086.
doi: 10.3762/bjoc.21.85. eCollection 2025.

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

Betty A Kustiana  1 , Galuh Widiyarti  1 , Teni Ernawati  1
Affiliations
Review

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

Betty A Kustiana et al. Beilstein J Org Chem. .

Abstract

Cinnamic acid derivatives represent a significant class of biologically active compounds exhibiting a broad spectrum of activities, such as antifungal, antidengue, antimetastatic, antimicrobial, antibacterial, and anticancer properties. Their preparation has attracted considerable attention due to their versatile applications across the pharmaceutical, food, and chemical sectors. This review elucidates the functional groups of cinnamic acid that are instrumental in the rational design of biologically active derivatives. A comprehensive representative of recent advancements in synthetic methodologies over the past five years is presented, particularly emphasizing the active scaffolds of bioactive cinnamic acid derivatives. The review provides a strategic overview of alternative synthetic routes and highlights the latest innovations, including more efficient, highly selective, and environmentally sustainable approaches. Given the widespread incorporation of the cinnamic acid framework in various therapeutic agents, this review delivers critical insights into a molecular design for hit-to-lead optimization, offering detailed synthetic strategies for diverse functional modifications. By critically examining these methodologies, the paper underscores their role in expanding the utility of cinnamic acid derivatives and addressing prevailing challenges.

Keywords: biologically active; cinnamic acid derivatives; environmentally sustainable; synthetic methodologies.

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Figures

Figure 1
Figure 1
Biologically active cinnamic acid derivatives.
Scheme 1
Scheme 1
General synthetic strategies for cinnamic acid derivatizations.
Scheme 2
Scheme 2
Cinnamic acid coupling via isobutyl anhydride formation.
Scheme 3
Scheme 3
Amidation reaction via O/N-pivaloyl activation.
Scheme 4
Scheme 4
Cinnamic acid amidation using TCCA/PPh3 reagent.
Scheme 5
Scheme 5
Cinnamic acid amidation using triazine-based reagents.
Scheme 6
Scheme 6
Cinnamic acid amidation using continuous flow mechanochemistry.
Scheme 7
Scheme 7
Cinnamic acid amidation using COMU as coupling reagent.
Scheme 8
Scheme 8
Cinnamic acid amidation using allenone coupling reagent.
Scheme 9
Scheme 9
Cinnamic acid amidation using 4-acetamidophenyl triflimide as reagent.
Scheme 10
Scheme 10
Cinnamic acid amidation using methyltrimethoxysilane (MTM).
Scheme 11
Scheme 11
Cinnamic acid amidation utilizing amine–borane reagent.
Scheme 12
Scheme 12
Cinnamic acid amidation using TCCA/PPh3 reagent.
Scheme 13
Scheme 13
Cinnamic acid amidation using PPh3/I2 reagent.
Scheme 14
Scheme 14
Cinnamic acid amidation using PCl3 reagent.
Scheme 15
Scheme 15
Cinnamic acid amidation utilizing pentafluoropyridine (PFP) as reagent.
Scheme 16
Scheme 16
Cinnamic acid amidation using hypervalent iodine(III).
Scheme 17
Scheme 17
Mechanochemical amidation using 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA) reagent.
Scheme 18
Scheme 18
Methyl ester preparation using tris(2,4,6-trimethoxyphenyl)phosphine (TMPP).
Scheme 19
Scheme 19
N-Trifluoromethyl amide preparation using isothiocyanate and AgF.
Scheme 20
Scheme 20
POCl3-mediated amide coupling of carboxylic acid and DMF.
Scheme 21
Scheme 21
O-Alkylation of cinnamic acid using alkylating agents.
Scheme 22
Scheme 22
Glycoside preparation via Mitsunobu reaction.
Scheme 23
Scheme 23
O/N-Acylation via rearrangement reactions.
Scheme 24
Scheme 24
Amidation reactions using sulfur-based alkylating agents.
Scheme 25
Scheme 25
Amidation reaction catalyzed by Pd0 via C–N cleavage.
Scheme 26
Scheme 26
Amidation reaction catalyzed by CuCl/PPh3.
Scheme 27
Scheme 27
Cu(II) triflate-catalyzed N-difluoroethylimide synthesis.
Scheme 28
Scheme 28
Cu/Selectfluor-catalyzed transamidation reaction.
Scheme 29
Scheme 29
CuO–CaCO3-catalyzed amidation reaction.
Scheme 30
Scheme 30
Ni-catalyzed reductive amidation.
Scheme 31
Scheme 31
Lewis acidic transition-metal-catalyzed O/N-acylations.
Scheme 32
Scheme 32
Visible-light-promoted amidation of cinnamic acid.
Scheme 33
Scheme 33
Sunlight/LED-promoted amidation of cinnamic acid.
Scheme 34
Scheme 34
Organophotocatalyst-promoted N–O cleavage of Weinreb amides to synthesize primary amides.
Scheme 35
Scheme 35
Cinnamamide synthesis through [Ir] photocatalyst-promoted C–N-bond cleavage of tertiary amines.
Scheme 36
Scheme 36
Blue LED-promoted FeCl3-catalyzed reductive transamidation.
Scheme 37
Scheme 37
FPyr/TCT-catalyzed amidation of cinnamic acid derivative 121.
Scheme 38
Scheme 38
Cs2CO3/DMAP-mediated esterification.
Scheme 39
Scheme 39
HBTM organocatalyzed atroposelective N-acylation.
Scheme 40
Scheme 40
BH3-catalyzed N-acylation reactions.
Scheme 41
Scheme 41
Borane-catalyzed N-acylation reactions.
Scheme 42
Scheme 42
Catalytic N-acylation reactions via H/F bonding activation.
Scheme 43
Scheme 43
Brønsted base-catalyzed synthesis of cinnamic acid esters.
Scheme 44
Scheme 44
DABCO/Fe3O4-catalyzed N-methyl amidation of cinnamic acid 122.
Scheme 45
Scheme 45
Catalytic oxidation reactions of acylating agents.
Scheme 46
Scheme 46
Preparation of cinnamamide-substituted benzocyclooctene using I(I)/I(III) catalysis.
Scheme 47
Scheme 47
Pd-colloids-catalyzed oxidative esterification of cinnamyl alcohol.
Scheme 48
Scheme 48
Graphene-supported Pd/Au alloy-catalyzed oxidative esterification via hemiacetal intermediate.
Scheme 49
Scheme 49
Au-supported on A) carbon nanotubes (CNT) and B) on porous boron nitride (pBN) as catalyst for the oxidative esterification of cinnamyl alcohol.
Scheme 50
Scheme 50
Cr-based catalyzed oxidative esterification of cinnamyl alcohols with H2O2 as the oxidant.
Scheme 51
Scheme 51
Co-based catalysts used for oxidative esterification of cinnamyl alcohol.
Scheme 52
Scheme 52
Iron (A) and copper (B)-catalyzed oxidative esterification of cinnamaldehyde.
Scheme 53
Scheme 53
NiHPMA-catalyzed oxidative esterification of cinnamaldehyde.
Scheme 54
Scheme 54
Synthesis of cinammic acid esters through NHC-catalyzed oxidative esterification via intermolecular oxidation.
Scheme 55
Scheme 55
Redox-active NHC-catalyzed esterification via intramolecular oxidation.
Scheme 56
Scheme 56
Electrochemical conversion of cinnamaldehyde to methyl cinnamate.
Scheme 57
Scheme 57
Bu4NI/TBHP-catalyzed synthesis of bisamides from cinnamalaldehyde N-tosylhydrazone.
Scheme 58
Scheme 58
Zn/NC-950-catalyzed oxidative esterification of ketone 182.
Scheme 59
Scheme 59
Ru-catalyzed oxidative carboxylation of terminal alkenes.
Scheme 60
Scheme 60
Direct carboxylation of alkenes using CO2.
Scheme 61
Scheme 61
Carboxylation of alkenylboronic acid/ester.
Scheme 62
Scheme 62
Carboxylation of gem-difluoroalkenes with CO2.
Scheme 63
Scheme 63
Photoredox-catalyzed carboxylation of difluoroalkenes.
Scheme 64
Scheme 64
Ru-catalyzed carboxylation of alkenyl halide.
Scheme 65
Scheme 65
Carboxylation of alkenyl halides under flow conditions.
Scheme 66
Scheme 66
Cinnamic acid ester syntheses through carboxylation of alkenyl sulfides/sulfones.
Scheme 67
Scheme 67
Cinnamic acid derivatives synthesis through a Ag-catalyzed decarboxylative cross-coupling proceeding via a radical mechanism.
Scheme 68
Scheme 68
Pd-catalyzed alkyne hydrocarbonylation.
Scheme 69
Scheme 69
Fe-catalyzed alkyne hydrocarbonylation.
Scheme 70
Scheme 70
Alkyne hydrocarboxylation using CO2.
Scheme 71
Scheme 71
Alkyne hydrocarboxylation using HCO2H as CO surrogate.
Scheme 72
Scheme 72
Co/AlMe3-catalyzed alkyne hydrocarboxylation using DMF.
Scheme 73
Scheme 73
Au-catalyzed oxidation of Au–allenylidenes.
Scheme 74
Scheme 74
Pd-catalyzed C–C-bond activation of cyclopropenones to synthesize unsaturated esters and amides.
Scheme 75
Scheme 75
Ag-catalyzed C–C-bond activation of diphenylcyclopropenone.
Scheme 76
Scheme 76
Cu-catalyzed C–C bond activation of diphenylcyclopropenone.
Scheme 77
Scheme 77
PPh3-catalyzed C–C-bond activation of diphenylcyclopropenone.
Scheme 78
Scheme 78
Catalyst-free C–C-bond activation of diphenylcyclopropenone.
Scheme 79
Scheme 79
Cu-catalyzed dioxolane cleavage.
Scheme 80
Scheme 80
Multicomponent coupling reactions.
Scheme 81
Scheme 81
Pd-catalyzed partial hydrogenation of electrophilic alkynes.
Scheme 82
Scheme 82
Nickel and cobalt as earth-abundant transition metals used as catalysts for the partial hydrogenation of conjugated alkynes.
Scheme 83
Scheme 83
Metal-free-catalyzed partial hydrogenation of conjugated alkynes.
Scheme 84
Scheme 84
Horner–Wadsworth–Emmons reaction between triethyl 2-fluoro-2-phosphonoacetate and aldehydes with either MeMgBr or n-BuLi as the base.
Scheme 85
Scheme 85
Preparation of E/Z-cinnamates using thiouronium ylides.
Scheme 86
Scheme 86
Transition-metal-catalyzed ylide reactions.
Scheme 87
Scheme 87
Redox-driven ylide reactions.
Scheme 88
Scheme 88
Noble transition-metal-catalyzed olefination via carbenoid species.
Scheme 89
Scheme 89
TrBF4-catalyzed olefination via carbene species.
Scheme 90
Scheme 90
Grubbs catalyst (cat 7)/photocatalyst-mediated metathesis reactions.
Scheme 91
Scheme 91
Elemental I2-catalyzed carbonyl-olefin metathesis.
Scheme 92
Scheme 92
Cu-photocatalyzed E-to-Z isomerization of cinnamic acid derivatives.
Scheme 93
Scheme 93
Ni-catalyzed E-to-Z isomerization.
Scheme 94
Scheme 94
Dehydration of β-hydroxy esters via an E1cB mechanism to access (E)-cinnamic acid esters.
Scheme 95
Scheme 95
Domino ring-opening reaction induced by a base.
Scheme 96
Scheme 96
Dehydroamination of α-aminoester derivatives.
Scheme 97
Scheme 97
Accessing methyl cinnamate (44) via metal-free deamination or decarboxylation.
Scheme 98
Scheme 98
The core–shell magnetic nanosupport-catalyzed condensation reaction.
Scheme 99
Scheme 99
Accessing cinnamic acid derivatives from acetic acid esters/amides through α-olefination.
Scheme 100
Scheme 100
Accessing cinnamic acid derivatives via acceptorless α,β-dehydrogenation.
Scheme 101
Scheme 101
Cu-catalyzed formal [3 + 2] cycloaddition.
Scheme 102
Scheme 102
Pd-catalyzed C–C bond formation via 1,4-Pd-shift.
Scheme 103
Scheme 103
NHC-catalyzed Rauhut–Currier reactions.
Scheme 104
Scheme 104
Heck-type reaction for Cα arylation.
Scheme 105
Scheme 105
Cu-catalyzed trifluoromethylation of cinnamamide.
Scheme 106
Scheme 106
Ru-catalyzed alkenylation of arenes using directing groups.
Scheme 107
Scheme 107
Earth-abundant transition-metal-catalyzed hydroarylation of α,β-alkynyl ester 374.
Scheme 108
Scheme 108
Precious transition-metal-catalyzed β-arylation of cinnamic acid amide/ester.
Scheme 109
Scheme 109
Pd-catalyzed β-amination of cinnamamide.
Scheme 110
Scheme 110
S8-mediated β-amination of methyl cinnamate (44).
Scheme 111
Scheme 111
Pd-catalyzed cross-coupling reaction of alkynyl esters with phenylsilanes.
Scheme 112
Scheme 112
Pd-catalyzed β-cyanation of alkynyl amide/ester.
Scheme 113
Scheme 113
Au-catalyzed β-amination of alkynyl ester 374.
Scheme 114
Scheme 114
Metal-free-catalyzed Cβ-functionalizations of alkynyl esters.
Scheme 115
Scheme 115
Heck-type reactions.
Scheme 116
Scheme 116
Mizoroki–Heck coupling reactions using unconventional functionalized arenes.
Scheme 117
Scheme 117
Functional group-directed Mizoroki–Heck coupling reactions.
Scheme 118
Scheme 118
Pd nanoparticles-catalyzed Mizoroki–Heck coupling reactions.
Scheme 119
Scheme 119
Catellani-type reactions to access methyl cinnamate with multifunctionalized arene.
Scheme 120
Scheme 120
Multicomponent coupling reactions.
Scheme 121
Scheme 121
Single atom Pt-catalyzed Heck coupling reaction.
Scheme 122
Scheme 122
Earth-abundant transition metal-catalyzed Heck coupling reactions.
Scheme 123
Scheme 123
Polymer-coated earth-abundant transition metals-catalyzed Heck coupling reactions.
Scheme 124
Scheme 124
Earth-abundant transition-metal-based nanoparticles as catalysts for Heck coupling reactions.
Scheme 125
Scheme 125
CN- and Si-based directing groups to access o-selective cinnamic acid derivatives.
Scheme 126
Scheme 126
Amide-based directing group to access o-selective cinnamic acid derivatives.
Scheme 127
Scheme 127
Carbonyl-based directing group to access o-selective cinnamic acid derivatives.
Scheme 128
Scheme 128
Stereoselective preparation of atropisomers via o-selective C(sp2)–H functionalization.
Scheme 129
Scheme 129
meta-Selective C(sp2)–H functionalization using directing group-tethered arenes.
Scheme 130
Scheme 130
para-Selective C(sp2)–H functionalization using directing group-tethered arenes.
Scheme 131
Scheme 131
Non-directed C(sp2)–H functionalization via electrooxidative Fujiwara–Moritani reaction.
Scheme 132
Scheme 132
Interconversion of functional groups attached to cinnamic acid.
Scheme 133
Scheme 133
meta-Selective C(sp2)–H functionalization of cinnamate ester.
Scheme 134
Scheme 134
C(sp2)–F arylation using Grignard reagents.
Scheme 135
Scheme 135
Truce–Smiles rearrangement of N-aryl metacrylamides.
Scheme 136
Scheme 136
Phosphine-catalyzed cyclization of γ-vinyl allenoate with enamino esters.
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