Recent Advances in the Synthesis of Propargyl Derivatives, and Their Application as Synthetic Intermediates and Building Blocks

Abstract

The propargyl group is a highly versatile moiety whose introduction into small-molecule building blocks opens up new synthetic pathways for further elaboration. The last decade has witnessed remarkable progress in both the synthesis of propargylation agents and their application in the synthesis and functionalization of more elaborate/complex building blocks and intermediates. The goal of this review is to highlight these exciting advances and to underscore their impact.

Keywords: application in synthesis; catalysts and catalytic systems; homopropargylic reagents; propargylated building blocks and intermediates; propargylating agents; target substrates.

Scheme 1

Propargyl–allenyl tautomerization process.

Scheme 2

Synthesis of homopropargyl alcohols 5/6 from isatin derivatives 4 and allenylboronic ester 2c.

Scheme 3

Synthesis of homopropargyl alcohols 8/9 from ketones 1 and allenylboronic acid 7.

Scheme 4

Synthesis of homopropargyl alcohols 11 from aldehydes/ketones 1 and allenyltrifluoroborate 10.

Scheme 5

Organosilver-catalyzed asymmetric synthesis of homopropargylic alcohols 13 from aldehydes 1 and propargylic silane reagents 12.

Scheme 6

Asymmetric synthesis of homopropargylic alcohols 15 from allenyltrichlorosilane 14 and aromatic aldehydes 1.

Scheme 7

Gold-catalyzed bispropargylation of xanthones and thioxanthones 16.

Scheme 8

Propargylation of carbonyl compounds 1, 21, 23, 25, and 27 with propargyl bromide 19a.

Scheme 9

Dual photoredox-mediated catalysis with titanium for the propargylation of aldehydes 1 with propargyl bromides 19a.

Scheme 10

Zinc(0)-mediated synthesis of homopropargyl alcohols 31.

Scheme 11

Cu-Catalyzed/Mn-mediated chemo-selective synthesis of homopropargyl alcohols 32.

Scheme 12

Bimetal redox synthesis of homopropargyl alcohols 34 from aldehydes 1 and propargyl bromide 19a.

Scheme 13

Zn-Mediated asymmetric propargylation of aldehydes 38 with allene gas 35 as reagent.

Scheme 14

Synthesis of 4-hydroxybut-2-ynoates 42 from carbonyl compounds and lithiated propynoates 41.

Scheme 15

Synthesis of propargyl epoxides 45 via propargylation of α-bromoketones 43 with the propargylic organozinc reagent 44.

Scheme 16

Pd⁰/Et₂Zn-mediated synthesis of 2-alkynylcyclopentanols 47 from carbonyl-tethered propargylic benzoates 46.

Scheme 17

Pd-mediated stereoselective Marshall allenylation of aldehyde 48 with (S)-propargylic mesylate 49.

Scheme 18

Three-component synthesis of homopropargylic alcohols 53 mediated by 3-(tributylstannyl)propargyl acetates 51 as propargylation reagents.

Scheme 19

Multimetallic protocols for the synthesis of homopropargylic alcohols 55/56 from propargylic carbonates 54.

Scheme 20

Gold-catalyzed synthesis of homopropargyl alcohol intermediates 58 from propargyl methylene-active derivatives 57 and aldehydes 1.

Scheme 21

Ru-catalyzed synthesis of (α-methyl)homopropargyl alcohols 61 from enyne 60 and aldehydes 1.

Scheme 22

Favorskii-type direct propargylation of carbonyl compounds 1 for the synthesis of propargyl alcohols 63/65 using a combination of Cs₂CO₃ and TEA as weak bases.

Scheme 23

Copper(I)-catalyzed stereodivergent anomeric propargylation of unprotected aldose 66 with allenylboronic acid pinacolate 2c.

Scheme 24

Copper(I)-catalyzed stereodivergent nucleophilic propargylation of the unprotected N-acetyl mannosamine 70 using 3-substituted allenylboronates 2c as nucleophiles.

Scheme 25

Diverse synthetic approaches of homopropargylamines 74 to the reaction of chiral sulfinylimines 73 and the silylated propargyl bromide 19a.

Scheme 26

Zn-mediated propargylation/lactamization cascade reaction of chiral 2-formylbenzoate-derived N-tert-butanesulfinyl imines 73 and silylated propargyl bromide 19a.

Scheme 27

Zn-promoted synthesis of mono and α,α-bispropargyl-substituted amines 79/78 from N-sulfonyl imidates 77 and various propargyl reagents 19a.

Scheme 28

Zinc-mediated propargylation of isatin-derived imines 80 using propargyl bromide 19a as propargylation reagent.

Scheme 29

Propargyl-/allenylboron-mediated synthesis of diverse propargyl derivatives 74/83/85/87 from imine substrates 73/82/84/86. In entries 2 and 3, the synthetic equivalent allenyl-Bpin 2c was used instead propargyl-Bpin 2a.

Scheme 30

Diastereoselective synthesis of enantiopure homopropargylic amines 74 via propargylation of sulfinylimines 73 with allenylzinc/propargylmagnesium bromides 88/89.

Scheme 31

Fe-catalyzed enantioselective synthesis of α-propargyl ketones 92/93 via controlled nitrosative degradation of the alkylidene isoxazol-5-ones 90/91.

Scheme 32

Three-component synthesis of dipropargylic amines 96 mediated by a thermally induced metal-free decarboxylative transition process.

Scheme 33

Synthesis of propargylamines 97 mediated by N-heterocyclic silylene-stabilized monocoordinated Ag(I) cationic complexed under solvent-free conditions.

Scheme 34

Synthesis of N,N-dipropargyl aminoalcohols 99 and N-propargyl oxazolidines100 via copper-catalyzed A³-type-coupling.

Scheme 35

Barium-induced Barbier-type propargylation of azo compounds 101 with propargylic halides 19.

Scheme 36

BF₃-catalyzed synthesis of ortho-propargyl iodobenzenes 104 from (diacetoxyiodo)arenes 103 and propargyl metalates 12.

Scheme 37

Synthesis of o-propargylated arylsulfide derivatives 106 via sulfoxide-directed, metal-free ortho-propargylation of sulfoxides 105.

Scheme 38

Metal- and heterobimetallic-catalyzed synthesis of diverse aryl-propargylated products 108 from propargyl alcohols 63.

Scheme 39

TFA-catalyzed synthesis of diverse aryl-propargyl derivatives 108 from the reaction of propargyl fluorides 19 with arenes 107 in DCM/HFIP solvent.

Scheme 40

Synthesis of propargylated polyfluoroarenes 108 from secondary propargyl phosphates 109 in the presence of tBuOLi/CuOAc.

Scheme 41

Boron-catalyzed sequential procedure for the synthesis of congested o-propargyl phenols 111.

Scheme 42

Direct Mn(I)/BPh₃ co-catalyzed synthesis of propargyl–indoles 114 using bromoallenes 19c as propargylating reagents.

Scheme 43

Synthesis of o-propargylated heteroaromatic sulfides 116 via sulfoxide-directed, metal-free ortho-propargylation of heteroaromatic sulfoxides 115.

Scheme 44

BF₃-catalyzed synthesis of ortho-propargyl iodothiophenes 119/120 from thiophenyliodine diacetates 117/118 and propargyl metalates 12.

Scheme 45

Direct Mn(I)/BPh₃ co-catalyzed synthesis of propargyl-heterocycles 125–128 using bromoallenes 19c as propargylating reagents.

Scheme 46

Different synthetic approaches to propargylated heterocycles 134–139 using propargyl alcohols 63.

Scheme 47

Synthesis of bis-homopropargylic alcohols 142 from 1,3-dilithiopropyne 141 and acid chlorides 140.

Scheme 48

Synthesis of N-propargylamines 97/144 from secondary propargyl alcohols 63.

Scheme 49

Cu-catalyzed synthesis of propargylamine intermediates 146 from propargylic alcohols 63 and amidine 145.

Scheme 50

Synthesis of tertiary propargylamine intermediates 150 through propargylation of secondary amines 149 with propargyl bromide 19a in the presence of calcium carbonate.

Scheme 51

Synthesis of 4-azaocta-1,7-diyne intermediates 152 through propargylation of homopropargylic amines 74 with propargyl bromide 19a.

Scheme 52

NaH-Catalyzed synthesis of N-propargyl-sulfoximines 155 via treatment of sulfoximines 154 with propargyl bromide 19a.

Scheme 53

Microwave-assisted synthesis of substituted N-propargyl isatins 156.

Scheme 54

Ultrasound-assisted synthesis of N-propargyl 4H-pyrano[2,3-d]pyrimidine derivatives 158 using TBAB as phase-transfer catalyst.

Scheme 55

NaH-catalyzed synthesis of N-propargylated heterocyclic compounds 160 using propargyl bromide 19a as propargylating agent.

Scheme 56

One-pot synthesis of nucleobase derivatives 165–168 via regioselective N-H functionalization of the DNA nucleobases 161–164 with propargyl bromide 19a.

Scheme 57

Synthesis of dipropargylamino-ester 171 using co-stabilized propargylic carbocation 170 as a propargylating agent, in the presence of BF₃•OEt₂/CAN as a catalytic system.

Scheme 58

Copper(I)-catalyzed synthesis of propargylated products 173 from trifluoromethyl stannylacrylates 172 and propargylic bromides 19a.

Scheme 59

The synthesis of O-propargyloxyamide intermediates 175 from hydroxyl-amides 174 and propargyl bromide 19a in the presence of potassium tert-butoxide as a base.

Scheme 60

Synthesis of O-propargyl intermediates 178 from the propargylation of (2-chloroquinolin-3-yl)methanol derivatives 177 with propargyl bromide 19a in the presence of calcium carbonate as a base.

Scheme 61

NaH-mediated synthesis of propargyl-perylenediimide 181 from the reaction of oxime 180 with propargyl bromide 19a.

Scheme 62

Alternative routes to propargylated ethers 183 and 186 via hydroxyderivatives 182 and 185.

Scheme 63

AgOTf-mediated synthesis of propargyl and both dicobalt complexes 189 from the reaction of gem-difluoropropargyl bromide dicobalt complex 188 with diversely substituted alcohols 187.

Scheme 64

K₂CO₃-catalyzed synthesis of O-propargylated compounds 191 from propargyl bromide 19a and hydroxy derivatives 187.

Scheme 65

Propargylation of the monosaccharides 192 and the hydroxylic precursors 193 from their reactions with propargyl esters 54.

Scheme 66

Amberlyst-15-mediated synthesis of end-propargylated glycosides 199.

Scheme 67

HBF₄-catalyzed synthesis of propargyl ethers 200 using propargylic alcohols 63 as propargylating agents.

Scheme 68

Synthesis of the propargylated amino-ethers 203 from aminoalcohols 201 with (Co₂(CO)₆)-propargyl ether complex 202 as propargylating agent.

Scheme 69

Synthesis of difluoropropargyl vinyl ether–dicobalt complexes 205 from carbonyl compounds 188 mediated by AgNTf₂ and iPr₂NEt or DTBMP bases.

Scheme 70

Propargylation of phenolic hydroxyl groups in precursors 206–209 using propargyl bromide 19a as propargylating agent.

Scheme 71

Synthesis of the propargylated tyrosine derivatives 215 from tyrosine analogues 214 and (Co₂(CO)₆)-propargylated complexes 202 as propargylating agents.

Scheme 72

Propargylation reactions of thiobenzimidazole- 216 and cysteine-containing peptides 217 with propargyl bromide 19a as propargylating agent.

Scheme 73

Synthesis of the propargylated cysteine ethyl ester derivatives 221 from cysteine analogues 220 and the (Co₂(CO)₆)-propargylated complex 170 as propargylating agent.

Scheme 74

Propargylation of the hydroxyl groups in carboxylic acids 223, 225, and 227 using propargyl bromide 19a and propargylamine 222.

Scheme 75

EDC-catalyzed synthesis of the propargylated prodrug 231 from O-propargylated hydroxylamine 230 and β-substituted-acrylic acid 229.

Scheme 76

Synthesis of the propargylated N-Bz-D-phenylalanine 232 from the phenylalanine derivative 227 and propargyl–dicobalt complex 170.

Scheme 77

Synthesis of propargyl-containing 1,3-dienyl derivatives 235/236 from dienyl phosphates 233/234 and allenyl-B-(pinacolato) 2c mediated by a sulfonate-containing NHC-Cu complex.

Scheme 78

Ag-Catalyzed synthesis of the 1,5-enynes 238 from the reaction of allylic phosphates 237 with propargyl organoboron compound 2a.

Scheme 79

Synthesis of the 1,5-enynes 240 from allyltrimethylsilane 239 and propargylic alcohols 63 in the presence of Bi(OTf)₃/[bmim][BF₄] catalytic system.

Scheme 80

FeCl₃•6H₂O-catalyzed synthesis of diarylalkenyl propargylic derivatives 242 using propargylic alcohols 63 as propargylating agents.

Scheme 81

Cooperative catalytic propargylation of quinones 243 mediated by Sc(OTf)₃ and Hantzsch ester (HE).

Scheme 82

Regio- and enantioselective Ni-catalyzed synthesis of chiral propargylamides 246.

Scheme 83

Gold-catalyzed synthesis of propargyl-1,3-amino ether derivatives 249 from C-alkynyl N-Boc-acetals 248 and allenamides 247.

Scheme 84

Synthesis of (E/Z)-3-amidodienynes 251 via tandem α-propargylation–1,3-H isomerization reaction of chiral allenamides 250 and propargyl bromides 19a and their Diels–Alder cycloadditions to produce cyclo-adducts 253.

Scheme 85

Synthesis of 1,4-oxopropargylated products 255 from propargylic alcohols 63 using Ph₃PAuCl/AgOTf as catalytic system.

Scheme 86

Ruthenium-mediated synthesis of secondary homopropargyl alcohols 256 from conjugated enyne substrate 60.

Scheme 87

Propargylations of diverse dicarbonylic/dicarboxylic compounds 257/259/260/263/265/266 with propargylic alcohols 63 mediated by Lewis and Brønsted acidic ILs using Sc(OTf)₃ or Bi(NO₃)₃•5H₂O as catalysts.

Scheme 88

Indium-mediated regioselective synthesis of propargyl aldehydes 270 from propargyl alcohols 63 using MacMillan reagent L* as chiral organocatalyst.

Scheme 89

IL/Bi-mediated synthesis of C-propargylated 4-hydroxycoumarins 271 from propargyl alcohols 63.

Scheme 90

Propargylation reactions of diverse methyne/methylene-active compounds 271/273/276/278/280 with propargyl bromides 19a.

Scheme 91

Synthesis of the γ-ketoacetylene 284 via a condensation reaction between propargyl chloride 282 and β-keto ester 283 in the presence of sodium hydride.

Scheme 92

Pd-catalyzed synthesis of difluoromethylene (CF₂)-skipped 1,4-diynes 286 from reaction of gem-difluoropropargyl bromide 285 with terminal alkynes 62.

Scheme 93

Asymmetric α-propargylation of α-branched aldehydes 204 mediated via primary amino acid catalyst.

Scheme 94

CuI/PPh₃-mediated Suzuki–Miyaura-type cross-coupling reaction for the synthesis of propargylated products 289 from propargyl electrophiles 19d/109 and diborylmethane 288.

Scheme 95

Copper-catalyzed diastereo- and enantioselective synthesis of propargylated compounds 291/293 using propargyl acetates 200 as propargylation reagents.

Scheme 96

Efficacy of the copper–ligand complexes in stereoselective α-propargylation of diverse carbonylic/carboxylic compound 294/296/298/301/302 with propargyl esters 200.

Scheme 97

Nickel/Lewis acid-catalyzed asymmetric synthesis of propargylic diesters 305.

Scheme 98

Copper-catalyzed synthesis of propargyl-substituted coumarins 307 from propargylic esters 200.

Scheme 99

Use of the bis(triphenylphosphine)palladium(II) dichloride-/Ag₂CO₃-/phosphine-based ligand L catalytic system for propargylation of 4-hydroxycoumarins 187b with propargylic carbonates 54.

Scheme 100

Zinc(II) chloride-catalyzed three-component and regioselective propargylation of enoxysilanes 309 with propargylic acetates 200.

Scheme 101

Re(I)- catalyzed synthesis of propargyl ethers 311 from hydropropargylation reaction between silyl enol ethers 309 and propargyl ether 191.

Scheme 102

Copper-catalyzed and microwave-assisted synthesis of propargyl intermediates 313 via propargylation of β-enamino compounds 312 with propargyl acetates 200.

Scheme 103

Copper-mediated diastereoselective synthesis of chiral propargylated cyclohexanones 316/317 from propargyl acetates 200 in the presence of the chiral tridentate P,N,N-ligand ((R)-L*).

Scheme 104

Synthesis of propargyl adducts 318 from a coupling reaction between 1,3-dicarbonyl compounds 257/259 and 1,3-diarylpropynes 57 in the presence of molecular oxygen, DDQ, and sodium nitrite.

Scheme 105

(S)-Proline-catalyzed three-component reductive coupling of propargyl aldehydes 319 with methylene-active compounds 320/321 in the presence of Hantzsch ester.

Scheme 106

Synthesis of propargylated alcohol 325 via catalytic asymmetric propargylation of the enolizable β-keto-lactone 324 with propargyl aldehyde 319.

Scheme 107

Bromo(alkynyl)zinc-mediated synthesis of o-propargylated phenols 327 from 2-(tosylmethyl)phenols 326.

Scheme 108

Synthesis of spiroketal derivatives 329 from propargyl derivatives 328 mediated by Co₂(CO)₆/BF₃•OEt₂ complex.

Scheme 109

Synthesis of propargylic and homopropargylic alcohols 331/332 from the reaction of acetylide 89 with epoxides 330.

Scheme 110

Synthesis of homopropargyl alcohols 13 via Rh-catalyzed C-C coupling of primary alcohols 187 with propargyl chlorides 19d.

Scheme 111

Blue LED-catalyzed synthesis of difluoropropargylated products 334 from alkenes 241 and silyl-protected bromodifluoropropyne 285 as propargylating agent.

Scheme 112

Enyne-mediated synthesis of homopropargylic alcohols 336 through radical carbonyl propargylation via dual chromium/photoredox catalysis.

Scheme 113

Synthesis of propargyl derivatives 190 and 144 from coupling reactions of propargyl bromides 285 and 19a with boronic acid reagents 337.

Scheme 114

Propargylation of chiral nonracemic mono- and poly-hydroxylated cyclic nitrones 338–340 with propargylated Grignard reagents (generated in situ) from TMS-propargyl bromide 19a.