Figure 1
Chemical structures of eugenol (1), methyleugenol (2) and isoeugenol (3).
Scheme 1
Reagents and conditions: (a) 1. O3, EtOH; 2. NaBH4, EtOH (98%); (b) AlI3, TBAI, MeCN, reflux (54%); (c) NaIO4, EtOAc; (d) Na2S2O4 (work-up, 78% overall); (e) Grubbs II in paraffin, cis-2- butene-1,4-diol, petroleum ether, room temperature (RT), 12 h (98%).
Scheme 2
Reagents and conditions: (a) BnBr, K2CO3, MeCN, RT, 4 h (98%); (b) 1. NaBH4, I2, THF, 0 °C, 2.5 h; 2. 9, RT, 3 h; 3. NaOMe, I2, 0 °C, 3 h (75%); (c) AgNO3, NaNO2, H2O, RT, 10 h (75%); (d) Ac2O, 4-dimethylaminopyridine (DMAP), CH2Cl2, RT, 5-6 h (85%); (e) Ra-Ni, H2 (30 psi), EtOH, 6 h; (f) Pd/C, H2, EtOH, 3 h (60%, overall).
Scheme 3
Reagents and conditions: (a) tert-Butyldimethylsilyl chloride (TBDMSCl), imidazole, 4-dimethylaminopyridine (DMAP), CH2Cl2 (90%); (b) NBS, H2O-DMSO (5:95), 0 °C, (78%); (c) Dess-Martin, CH2Cl2 (78%); (d) TBDMSCl, imidazole, DMAP, CH2Cl2 (90%); (e) K2CO3, tetrahydrofuran (THF), MeOH, 30 min, RT (90%); (f) NaOH (aq.), nBu4NBr, toluene, RT, 12-14 h (57%); (g) 1. HF (aq.), MeCN, RT, 30 min; 2. 8% NaOH (10%).
Scheme 4
Reagents and conditions: (a) TBSCl, imidazole, dimethylformamide (DMF), RT, 19 h (78%); (b) 1. disiamylborane, 0 °C, 3 h; 2. PCC, CH2Cl2, reflux, 2 h (75%); (c) SAMP, 0 °C → RT, 20 h (84%); (d) 1. lithium di-isopropyl amide (LDA), 0 °C, 5.5 h; 2. benzyloxymethyl chloride (BOMCl), −120 °C, 20 min, then RT, 20 h (77%); (e) nBuLi (2 equiv.), 29 (2 equiv.), THF, 0 °C, 30 min → RT, 19 h (30, 72%); (f) PhSSiMe3 (10 equiv.), nBu4NI (1.5 equiv.), ZnI2 (5 equiv.), 1,2-dichloroethane (DCE), RT (31, 65%); (g) tetra-n-butylammonium fluoride (TBAF) (3.3 equiv.), THF, RT, 30 min (22, 82%); (h) O3, CH2Cl2, −78 °C, 30 min (79%); (i) TMSOTf (cat.), CH2Cl2, −78 °C, 3 h, then 0 °C, 1 h (76%).
Scheme 5
Reagents and conditions: (a) 1. i-PrMgCl, THF, 30 min, −78 °C; 2. 1,3-dibromo-5,5-dimethyl hydantoin, 3 h, −78 °C (78%); (b) MeI, K2CO3, DMF, 2 h, RT (90%); (c) 4-HO–C6H4CH2CH=CH2, Cs2CO3, CuI, N,N-dimethylglycine hydrochloride, dioxane, 90 °C, 48 h (75%); (d) BBr3, CH2Cl2, 30 min, −78 °C, RT, 2 h (75%).
Scheme 6
Reagents and conditions: (a) 1. BH3·SMe2, THF; 2. H2O2, NaOH (84%); (b) CH2=CHCH2Br, K2CO3, Me2CO (83%); (c) 1. N,N’- dimethylaniline, Δ (100%); 2. NaOtBu, DMSO, Δ (69%); (d) 1. PivCl, DMAP, pyridine, CH2Cl2 (83%); 2. CH2=CHCH2SiMe2Cl, Et3N, CH2Cl2 (86%); (e) Grubbs II, CH2Cl2, Δ (75%); (f) BF3·OEt2, CH2Cl2; (g) 1. OsO4, KIO4, THF-H2O (95% from 45; 91% from 46); 2. LiAlH4, THF, –60 °C (37, 84%; 38, 90%).
Scheme 7
Reagents and conditions: (a) 1. NaH, THF; 2. ClPO(NMe2)2 (97%); (b) 1. sBuLi; 2. MeI (96%); (c) 1. sBuLi; 2. MeI (96%); (d) sBuLi, tetramethylethylenediamine (TMEDA), 3,4-(MeO)2C6H3CHO, −108 °C (71%); (e) LiAlH4 (51%); (f) AcOH (41%).
Scheme 8
Reagents and conditions: (a) 1. BH3·SMe2, THF; 2. H2O2, NaOH (84%); (b) 1. Ac2O, BF3.Et2O, THF, 0 °C, 5 h (77%); (c) NBS, Et2NH, CH2Cl2, RT, 16 h (39%); (d) CuC≡C(4-BnO-3-MeO)Ph, pyridine, 115 °C, 20 h (ca. 65%); (e) 5% Pd/C, AcOH-THF, RT, 10 h (ca. 92%); (f) 1. Zn(CN)2, HCl, KCl, Et2O, 0 °C, 30 min; 2. EtOH-H2O, 50 °C (ca. 59%).
Scheme 9
Reagents and conditions: (a) Hexamine, AcOH, 125 °C (30%); (b) PPh3MeBr, nBuLi, THF, 0 °C → RT (81%); (c) Rh(COD) OMe2 (4 mol%), bis(dicyclohexylphosphino)methane (dcpm, 8 mol%), dioxane, 70 °C, 24 h; (d) trifluoroacetic acid (TFA), CH2Cl2 (1:20), 40 °C, 3 h (60, 78%; 61, 82%, overall).
Scheme 10
Reagents and conditions: (a) 1. TBSCl, imidazole, DMF, RT, 4 h (45%); 2. MgCl2, (CH2O)n, Et3N, THF, 70 °C, 2.5 h (87%); 3. MeI, Ag2O, Et2O, RT, 10 h (81%); (b) PPh3EtBr, BuLi, THF, RT, 2 h (63%); (c) 1. Grubbs II (0.1 equiv.), CH2Cl2, 50 °C, 8 h (85%); 2. TBAF, THF, RT, 30 min (48%); (d) TBSCl, imidazole, DMAP (cat.), DMF, RT, 3 h (96%); (e) 1. (TMP)2Zn.MgCl2.2LiCl, THF, RT, 1 h; (f) 76, Pd(OAc)2 (5 mol%), SPhos (10 mol%), PhMe, 65 °C, 2 h (84% overall); (g) DIBAL-H, CH2Cl2 (85%); (h) HClO4 (8 equiv.), AcOH, RT, 9 h (76%); (i) 2,6-di-tert-butyl pyridine, MeCN, 0 °C, 10 min (89%); (j) 82 (2.5 equiv.), MeCN/ MeOH (5:1), 80 °C (62%); (k) Br2, CCl4, −10 °C, 5 min (98%); (l) TBSCl, imidazole, DMAP (cat.), DMF, RT, 45 min (96%).
Scheme 11
Reagents and conditions: (a) NaH, BnBr, DMF, 0 °C, 1 h (100%); (b) 1. OsO4 (cat.), N-methylmorpholine-N-oxide (NMO), tBuOH:H2O:THF (2:1:4), RT, 1 h; 2. NaIO4 CH2Cl2-H2O (1:1), 0 °C, 40 min (100%); (c) N2CHCOOEt, SnCl2 (cat.), CH2Cl2, −72°C, 5 min, RT, overnight (92%); (d) 87, piperidine, PhCOOH, benzene, reflux, 2.5 h (80%, after one cycle, E/Z = 5:3); (e) (S,S)-TADOOH (cat.), LiOH, THF, 0 °C, 6 h; RT, overnight (83%, ee = 98%); (f) TfOH (4 mol%), CH2Cl2, −10 °C → RT, 15 min (89, 70%; 89a, 17%); (g) ClSi(Me)2CH2Br, imidazole, DMF, RT, 1 h (75%; 94% brsm); (h) SmI2, NiI2 (0.1 equiv.), THF, 0 °C, 1 h (58%); (i) 35% H2O2, NaHCO3, MeOH-THF, RT, overnight (87%; 90% brsm); (j) nPrSNa, DMF, 50 °C, 24 h (97%); (k) 1. H2 (1 atm), Pd/C, MeOH, RT, 4 h; 2. Dowex-50, MeOH (72% overall).
Scheme 12
Reagents and conditions: (a) 2, BF3·Et2O, CH2Cl2, –78 °C, 15 min, –30 °C, 30 min (88%); (b) OsO4 (cat.), NMO, Me2CO-H2O-tBuOH (4:2:1) overnight, RT; (c) NaIO4, THF-H2O (3:1) overnight, RT (89%, overall); (d) NaBH4, MeOH-Et2O (4:1), 0 °C, 15 min (92%); (e) 1. Na, NH3, –33 °C; 2. NH4Cl, –33 °C → RT (83%); (f) PPh3, diethyl azodicarboxylate (DEAD), HBF4, THF, reflux (82%).
Scheme 13
Reagents and conditions: (a) Pd(PPh3)4, NaHCO3, DMF, reflux, 24 h (65%); (b) LDA (2 equiv.), THF, −78 °C, 2 h, then RT 2 h (76%); (c) H2O2, I2, H2SO4, MeOH (62%); (d) homoveratrylamine (106), EtOH, RT, 24 h (80%); (e) 1. LDA (2 equiv.), THF, −78 °C; 2. methyl homoveratrate (109, 1 equiv.), THF, −78 °C, 2 h then RT, 2 h (110, 73%; 108, 15%); (f) 2M HCl, CH2Cl2, RT, 5 h (100%); (g) BBr3, CH2Cl2 (73%).
Scheme 14
Reagents and conditions: (a) BnBr, TBAI (cat.), K2CO3, DMF, 55 °C, 16 h (99%); (b) OsO4, NMO, THF-H2O, RT, 16 h; (c) NaIO4, THF-H2O, RT, 4 h; (d) 113, CH2Cl2, RT, 12 h (93% overall); 2. LiAlH4, THF, −10 °C, 20 min; RT, 1.5 h (88%); (e) 1. L-(+)-DIPT, Ti(OiPr)4, t-butyl hydroperoxide (TBHP), CH2Cl2, −25 °C (98%, ee = 91%); 2. ClMgCH2CH=CH2, THF, −20 °C; 3. TsCl, nBu2SnO, Et3N, CH2Cl2 (91%); (f) 1. K2CO3, MeOH (100%); 2. LiBr.H2O, AcOH, THF, 90 °C (91%); (g) 1. OsO4, NMO; 2. NaIO4, THF-H2O (2:1) (85%); (h) Bi(OTf)3 (5 mol%), LiClO4, CH2Cl2, 3.5 h; (i) H2, Pd/C, THF; (j) TBAF, xylene, 130 °C, 4 h (86% overall); (k) 1. 121 (20 mol%), 122 (5 equiv.), dioxane, 60 °C, 130 h; 2. H2, Pd/C, EtOAc-ethanolic KOH (2:1) (73% overall); (l) AlCl3, TBAI, MeCN-CH2Cl2 (2:1), 0 °C (83%); (m) 1. MsCl, Et3N, CH2Cl2, 0 °C to RT; 2. LiBr.H2O, Li2CO3, DMSO, 150 °C (72% overall); (n) potassium bis(trimethylsilyl)amide (KHMDS), MeI, THF-HMPA, −78 °C → −10 °C (80%); (o) H2C =CHCO2
tBu, KOtBu, tBuOH, THF, −10 °C → 0 °C (62%); (p) TFA, CH2Cl2, 0 °C (100%); (q) 1. 129, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), Et3N, DMF (71%); 2. 2 mol L−1 KOH (aq.), dioxane-MeOH, 35 °C (60%).
Scheme 15
Reagents and conditions: (a) 1 (3 equiv.), Grubbs II (2.5 mol%), CH2Cl2, reflux (70%); (b) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.1 equiv.), THF, RT, overnight (52%).
Scheme 16
Reagents and conditions: (a) K3Fe(CN)6, O2, NH4OH, Me2CO-H2O, RT (95%); (b) K2CO3, CH3I, DMF, 60 °C, 8 h (90%); (c) AlCl3, Me2S, RT, 1 h (134d:134e = 1:4, 95%); (d) (1R,2S,5R)-(−)-menthyl chloroformate, Et3N, PhMe, RT, 1 h (95%); (e) BTEA.Br3 (10 equiv.); (f) 1. ZnCl2, AcOH, 80 °C, 24 h (aS, 90%; aR, 95%); 2. LiAlH4, THF, 0 °C → RT (aS137, 89%; aR137, 90%).
Scheme 17
Reagents and conditions: (a) 1. 70% HNO3, AcOH (79%); 2. OsO4, NaIO4, THF-H2O 0 °C → RT (82%); (b) 140, 141, NaI, MeOH (24%); (c) BBr3, CH2Cl2, RT (92%); (d) H2, Pd/C, EtOH (90%); (e) H2, Pd/C, EtOAc (77%).
Figure 2
Selected synthetic bioactive compounds prepared from eugenol.
Figure 3
Selected synthetic bioactive compounds prepared from eugenol.
Scheme 18
Reagents and conditions: (a) 10% KOH/Al2O3 (88%); (b) 10% BF3.Et2O, MeCN, 60 ºC, 6-10 h (40-64%); (c) ClCH2CO2Na; (d) HNO3, AcOH, –5 ºC, 4 h; RT, 4 h (80%); (e) 1. S2O4Na2, conc. NH3, RT, 6 h; 2. AcOH, 72 h (68%).
Scheme 19
Reagents and conditions: (a) KOH, 18-crown-6, PhH, 40- 60 °C, 2 h (ca. 100%); (b) AcOH, conc. H2SO4, 50-60 °C; 30 min or 94% H2SO4, 0 °C → RT, 15 min (52-82%); (c) AcOH, conc. H2SO4, 50-60 °C; 30 min (R = Me, R1 = NH2, 77%; R = Et, R1 = NH2, 73%); or 94% H2SO4, 0 °C → RT, 15 min (R = Me, R1 = OEt, 22%); (d) AcOH, conc. H2SO4, 50-60 °C; 30 min (54%); (e) 54% HBF4, Et2O, overnight (36%); (f) 163, TfOH, CH2Cl2, −20 °C, 1 h (84%); (g) dimethyl acetylenedicarboxylate (DMAD), PPh3, MeCN, MW (70%).
Scheme 20
Reagents and conditions: (a) 1, H2CO, PhMe, 210 °C (78%).
Scheme 21
Reagents and conditions: (a) Diol 169; PhH, reflux, Et3N, 0 °C → RT, 9 h; (b) 1, N,N’-dicyclohexylcarbodiimide (DCC), DMAP, CH2Cl2, 0 °C, 6 h (76%); (c) CsCl, Grubbs I (5 mol%), CH2Cl2, reflux, 36 h (67%, E:Z = 2:1).
Scheme 22
Reagents and conditions: (a) 173, K2CO3, DMSO, 80 °C, 8 h (50%); (b) 1. 200 °C, 5 h (35%); 2. CuCl2, Zn(AcO)2, CoCl2, NiCl2, Fe(CO)5, quinoline, 200 °C, 24 h (24-39%; M = Cu, Co, Ni, Zn, Fe).
Scheme 23
Reagents and conditions: (a) 1. NaNO2, HCl, 0-5 °C; (b) 1, NaOH (73%); (c) K2CO3, DMF, MW (360 W), 10 min (76%); (d) CuCl2, Zn(AcO)2, CoCl2, NiCl2, DBU, DMF, MW (360 W), 10 min (M = Co, Ni, Cu, Zn).
Scheme 24
Reagents and conditions: (a) 184 (R = Cl, Br), tungstosilicic acid, H2O, reflux, 6 h; (R = Br, 81%; R = Cl, 80%); (b) K3Fe(CN)6; (c) H2CO, AcOH, HCl. BEG: bis-eugenol.
Scheme 25
Formation of some 1/1, 1/2 and 1/3 adducts between eugenol and 4,4’-bismaleimidediphenyl methane (186).
Scheme 26
Synthesis and degradation of the eugenol-ethylenediamine-tetraacetic acid (EDTA) poly(anhydride-ester) 193.
Scheme 27
Reagents and conditions: (a) AlCl3, 80 °C, 1.5 h (ca. 85%); (b) CNBr, Et3N, Me2CO, −15 °C, 1.5 h (87%); (c) 100 °C, 30 min; 150 °C, 30 min; 200 °C, 60 min; 250 °C, 3 h; (d) Grubbs I (0.4 mol%), 2.67 kPa, 48 h (93%); (e) H2 (40-50 psi), 10% Pd/C, EtOH, 3 h (ca. 100%); (f) CNBr, Et3N, Me2CO, −50 °C → 10 °C, 1.5 h (73%); (g) 1. triphosgene, pyridine, −15 °C; 2. overnight, RT; 3. MeOH, 50 °C, 30 min (57% overall); (h) 150 °C, 30 min; 201 °C, 24 h.
Scheme 28
Reagents and conditions: (a) H2CO, DMSO, 130 °C, 5 h (80%); (b) 1. BnNMe3
+OH-, H2O; 2. fuming HNO3, RT, 20 h (90%); 3. 10% Pd/C, Et3N, HCO2H, THF, 60 °C, 5 h (82%).
Scheme 29
Reagents and conditions: (a) Pt complex, C6H5Cl, reflux.
Scheme 30
and conditions: (a) K2CO3, 1,2-Cl2-C6H4, DMSO, 180 °C.
Scheme 31
Reagents and conditions: (a) Acryloyl chloride, Et3N, Et2O, RT, 48 h (ca. 80%); (b) 1. ClCH2CH2OH, KI, KOH, EtOH, reflux, 24 h; 2. acryloyl chloride, Et3N, Et2O, RT, 48 h (ca. 80%); (c) azobisisobutyronitrile (AIBN), PhMe, 50 °C, 24 h.
Scheme 32
Reagents and conditions: (a) HCO2H, 220 °C, 24 h (60%); (b) NaOH, EtOH, 30 °C, 2 h (97%); (c) COCl2, Et3N, Et2O, 0 °C, overnight (86%); (d) L-alanine, NaHCO3, Et2O-H2O, RT, 5 h (70%); (e) for 220: 1. isobutyl chloroformate, NMO, THF, 0 °C; 2. propargylamine, RT, 1 h (75%). For 221: propargyl alcohol, EDCI.HCl (95%).
Scheme 33
Biotransformation of eugenol into other valuable compounds.
Figure 4
Selected relevant eugenyl glycosides.