4674-50-4

Basic information

• Product Name: NOOTKATONE
• Synonyms: NOOTKATONE;FEMA 3166;(+)-5,6-dimethyl-8-isopropenylbicyclo[4.4.0]dec-1-en-3-one;2(3h)-naphthalenone,;2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-4,4a-dimethyl-6-(1-methylethenyl)-, [4R-(4alpha,4aalpha,6beta)]-;2(3H)-Naphthalenone,4,4a,5,6,7,8-hexahydro-4,4a-dimethyl-6-(1-methylethenyl)-,[4R-(4.alpha.,4a.alpha.,6.beta.)]-;4,4a,5,6,7,8-hexahydro-4,4a-dimethyl-6-(1-methylethenyl)-,[4R-(4.alpha.,4a.alpha.,6.beta.)]-2(3H)-Naphthalenone;4,4a,5,6,7,8-hexahydro-4,4a-dimethyl-6-(1-methylethenyl)-2(3h)-naphthalenon
• CAS NO: 4674-50-4
• Molecular Formula: C₁₅H₂₂O
• Molecular Weight: 218.33
• EINECS: 225-124-4
• Product Categories: Chiral Building Blocks;Ketones;Organic Building Blocks
• Mol File: 4674-50-4.mol
• Article Data: 34

Chemical Properties

• Melting Point: 35-39 °C
• Boiling Point: 125°C 0,5mm
• Flash Point: 99°C
• Appearance: colourless crystal
• Density: 0,997 g/cm3
• Vapor Pressure: 0.000358mmHg at 25°C
• Refractive Index: n20/D 1.52
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Ethanol (Slightly), Methanol (Slightly)
• Water Solubility: Slightly soluble in ethanol and chloroform. Partly soluble in water.
• Stability: Stable. Incompatible with strong oxidizing agents.
• BRN: 4676969
• CAS DataBase Reference: NOOTKATONE(CAS DataBase Reference)
• NIST Chemistry Reference: NOOTKATONE(4674-50-4)
• EPA Substance Registry System: NOOTKATONE(4674-50-4)

Safety Data

• Safety Statements: 23-24/25
• WGK Germany: 2
• TSCA: Yes
• Hazardous Substances Data: 4674-50-4(Hazardous Substances Data)

Usage

Description

NOOTKATONE is a bicyclic conjugated sesquiterpene ketone with a grapefruit-like flavor, commonly used in the fragrance, food, cosmetics, and pharmaceutical industries. It is known for its diverse biological activities, including being an effective repellent and insecticide against various insects, and for its antiplatelet effect in traditional medicine.

Uses

Used in Insect Repellent and Insecticide Applications:
NOOTKATONE is used as an effective repellent and insecticide for mosquitoes, bed bugs, head lice, and other insects. It is particularly effective against deer ticks and lone star ticks when applied in spray form.
Used in Flavoring Industry:
NOOTKATONE is used as a flavoring agent for beverages, thanks to its powerful fruity sweet, citrusy, and grapefruit peel oil-like aroma.
Used in Fragrance Industry:
NOOTKATONE is used in the fragrance industry due to its pleasant grapefruit-like scent.
Used in Cosmetics Industry:
NOOTKATONE is used in the cosmetics industry for its diverse biological activities and pleasant aroma.
Used in Pharmaceutical Industry:
NOOTKATONE is used in the pharmaceutical industry as the active ingredient responsible for the antiplatelet effect of Cyperus rotundus, a well-known oriental traditional medicine. It also shows promising efficacy against Staphylococcus aureus biofilms.
Used in Wood Protection:
NOOTKATONE is used in the wood protection industry to reduce tunnel lengths, feeding, and survival rates in termites when wood is pretreated with the compound.
Used in Antiplatelet Applications:
NOOTKATONE is used as an antiplatelet agent, inhibiting platelet aggregation induced by collagen, thrombin, and arachidonic acid at concentrations ranging from 10 to 100 μM.
Used in Weight and Glucose Management:
NOOTKATONE is used in the management of body weight and plasma glucose levels in mice fed a high-fat and high-sucrose diet, with a dose-dependent effect at concentrations ranging from 0.1 to 0.3%.

Preparation

By oxidation of valencene (a sesquiterpene) with tertiary butyl chromate.

InChI:InChI=1/C15H22O/c1-10(2)12-5-6-13-8-14(16)7-11(3)15(13,4)9-12/h8,11-12H,1,5-7,9H2,2-4H3/t11-,12-,15+/m1/s1

Synthetic route

(4R,4aS,6R)-4,4a,5,6,7,8-Hexahydro-4,4a-dimethyl-6-(1-chloro-1-methylethyl)-2(3H)-naphthalenone (72453-44-2) → (+)-nootkatone (4674-50-4)

Conditions	Yield
With sodium acetate In water; acetic acid at 100℃; for 2h;	93%
With sodium acetate; acetic acid at 100℃; for 2h; Inert atmosphere;	93%
With sodium acetate; acetic acid at 100℃; for 2h;	93%
With aluminum oxide In hexane at 60℃; for 24h; Yield given;

valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) + semicarbazide hydrochloride (563-41-7) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Stage #1: valencene With manganese(IV) oxide In dichloromethane at -25℃; for 0.5h; Stage #2: With tert.-butylhydroperoxide In dichloromethane; water at -10℃; for 9h; Reflux; Stage #3: semicarbazide hydrochloride Further stages;	83%

valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) → (+)-nootkatone (4674-50-4)

Conditions	Yield
With Czapek-pepton medium; Pallavicinia subcilita at 30℃; for 168h; pH=7.0;	82%
With pyridine; tert.-butylhydroperoxide; N-hydroxy-3,4,5,6-tetrachlorophthalimide; lithium perchlorate In acetone Reagent/catalyst; Solvent; Electrochemical reaction; chemoselective reaction;	77%
With tert.-butylhydroperoxide; sodium chlorite In water; acetonitrile at 50℃; for 18h; Product distribution / selectivity;	72%

valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) → phthalimide (136918-14-4) + (+)-nootkatone (4674-50-4) + 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2-ol (840474-83-1)

Conditions	Yield
With oxygen; N-hydroxyphthalimide; cobalt nitrate; cobalt(II) acetate; cobalt(III) acetylacetonate In acetonitrile at 40℃; under 9750.98 Torr; for 3h; Product distribution / selectivity;	A n/a B 67.9% C 5.6%
With oxygen; N-hydroxyphthalimide; cobalt(II) acetate; cobalt(III) acetylacetonate In acetonitrile at 40℃; under 9750.98 Torr; for 4h; Product distribution / selectivity;	A n/a B 53.7% C 1.4%

(4R,4aS,6R)-2-hydroperoxy-4,4a-dimethyl-6-(prop-1-en-2-yl)-2,3,4,4a,5,6,7,8-octahydronaphthalene (329309-57-1) → (+)-nootkatone (4674-50-4) + 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2-ol (840474-83-1)

Conditions	Yield
With lyophilisate of Pleurotus sapidus In aq. buffer at 20℃; for 48h; pH=7.4; Enzymatic reaction;	A 16% B 7%

β-gurjunene (17334-55-3) → valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) + (+)-nootkatone (4674-50-4)

Conditions	Yield
With culture medium of Mucor species; Czapek-pepton medium at 30℃; for 168h;	A 0.7% B 0.6%

(4R,6R,10S)-4,10-dimethyl-6-(1‘-hydroxyisopropyl)-1-en-3,4,5,6,7,8-hexahydronaphthalen-2-one (20489-50-3) → (+)-nootkatone (4674-50-4)

Conditions	Yield
With pyridine; trichlorophosphate

(4R,4aS,6R)-4,4a,5,6,7,8-Hexahydro-4,4a-dimethyl-6-(1-chloro-1-methylethyl)-2(3H)-naphthalenone (72453-44-2) → (4R,4aS)-(+)-4,4a-dimethyl-6-isopropylidene-4,4a,5,6,7,8-hexahydro-(3H)-naphthalen-2-one (15764-04-2) + (+)-nootkatone (4674-50-4)

Conditions	Yield
With aluminum oxide In hexane at 60℃; for 24h;

valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) → (2R,4aR,8R,8aS)-2-Isopropenyl-8,8a-dimethyl-1,3,4,7,8,8a-hexahydro-2H-naphthalen-4a-ol (50763-63-8) + 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2β-ol (50763-66-1) + 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2α-ol (50763-67-2) + (+)-nootkatone (4674-50-4) + (4R,4aS,6R)-6-Isopropenyl-4,4a-dimethyl-1,2,3,4,4a,5,6,7-octahydro-naphthalen-1-ol (32420-34-1, 32420-35-2, 50763-64-9, 50763-65-0, 53643-08-6)

Conditions	Yield
Mechanism; Product distribution; multistep reaction: photooxygenation + reduction; reaction with triplet and singlet oxygen;

2-Methyl-4-isopropenyl-6-n-butylthiomethylen-cyclohexanon (67779-29-7) + trans-3-penten-2-one (3102-33-8) → (+)-nootkatone (4674-50-4)

Conditions	Yield
(i) KOtBu, tBuOH, (ii) aq. KOH; Multistep reaction;

tert.-butylhydroperoxide (75-91-2) + valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) → (+)-nootkatone (4674-50-4) + 2β-t-butylperoxy-4α,5α,7β-eremophila-1(10),11-diene + 9β-t-butylperoxy-2-oxo-4α,5α,7β-eremophila-1(10),11-diene

Conditions	Yield
With copper(l) iodide In acetonitrile at 50℃; for 18h; Substitution; oxydation;	A 260 mg B 31 mg C n/a

valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) → 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2α-ol (50763-67-2) + (+)-nootkatone (4674-50-4) + (-)-2-(2R)-(1,2,3,4,6,7,8,8a-octahydro-8α,8aβ-dimethyl-2α-naphthalenyl)-2-propen-1-ol

Conditions	Yield
With chicory; enzymes from roots of Cichorium intybus L; NADPH In ethanol for 1h; pH=7.5; Product distribution; Further Variations:; Reagents;

valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) → (+)-(4R,5S,7R,11S)-11,12-epoksynootkatone + 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2β-ol (50763-66-1) + (+)-nootkatone (4674-50-4) + (1aR,4R,4aS,6R,8aS)-4,4a-dimethyl-6-(prop-1-en-2-yl)octahydro-1aH-naphtho[1,8a-b]oxirene

Conditions	Yield
With 1,4-dihydronicotinamide adenine dinucleotide; cytochrome P450BM-3 Product distribution; Enzyme kinetics; Further Variations:; Reagents;

valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) → 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2α-ol (50763-67-2) + (+)-nootkatone (4674-50-4) + 9α-hydroxy-2-oxo-4α,5α,7β-eremophila-1(10),11-diene (226546-99-2)

Conditions	Yield
With 1,4-dihydronicotinamide adenine dinucleotide; cytochrome P450cam In ethanol Product distribution; Enzyme kinetics; Further Variations:; Reagents;

valencene (10219-75-7, 22343-24-4, 24741-64-8, 68773-84-2, 4630-07-3) → 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2β-ol (50763-66-1) + 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2α-ol (50763-67-2) + (+)-nootkatone (4674-50-4)

Conditions	Yield
With Botryosphaeria dothidea (Ume BD8398II); Czapek-pepton medium at 30℃; for 168h; pH=7.0;	A 31 % Chromat. B 18 % Chromat. C 43 % Chromat.

4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2β-ol (50763-66-1) → (+)-nootkatone (4674-50-4)

Conditions	Yield
With Chlorella pyrenoidosa for 24h;

4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2α-ol (50763-67-2) → (+)-nootkatone (4674-50-4)

Conditions	Yield
With Chlorella fusca for 24h;
Multi-step reaction with 2 steps 1: 42 percent / p-nitrobenzoic acid; triphenylphosphine; diethyl azodicarboxylate 2: Chlorella pyrenoidosa / 24 h View Scheme

(1R,5S)-(+)-nopinone (38651-65-9) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 8 steps 1: 88 percent / triethylamine / dimethylformamide / 24 h / 95 °C 2: 96 percent / TiCl4 / CH2Cl2 / 1.5 h / -78 °C 3: 90 percent / p-toluenesulfonic acid / benzene / 2 h / Heating 4: 81 percent / TiCl4 / CH2Cl2 5: 71 percent / NaNH2 / benzene 6: 1.) O3; 2.) Zn/CH3COOH / 1.) -78 deg C, 30 min; 2.) room temperature overnight. 7: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 8: Al2O3 / hexane / 24 h / 60 °C View Scheme
Multi-step reaction with 8 steps 1: 88 percent / triethylamine / dimethylformamide / 24 h / 95 °C 2: 96 percent / TiCl4 / CH2Cl2 / 1.5 h / -78 °C 3: 90 percent / p-toluenesulfonic acid / benzene / 2 h / Heating 4: 89 percent / TiCl4 / CH2Cl2 / 2 h / -78 °C 5: 72 percent / NaNH2 / benzene / 1.) reflux, 5 h; 2.) 45 deg C, 17.5 h. 6: 1.) mercuric acetate; 2.) LiCl, PdCl2, CuCl2. / 1.) room temperature, CH3OH, 15 min; 2.) 55 deg C, CH3OH, 1 hour. 7: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 8: Al2O3 / hexane / 24 h / 60 °C View Scheme
Multi-step reaction with 7 steps 1: 55 percent / N-methylaniline, EtMgBr / benzene; diethyl ether / 1 h / 0 °C 2: 90 percent / p-toluenesulfonic acid / benzene / 2 h / Heating 3: 81 percent / TiCl4 / CH2Cl2 4: 71 percent / NaNH2 / benzene 5: 1.) O3; 2.) Zn/CH3COOH / 1.) -78 deg C, 30 min; 2.) room temperature overnight. 6: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 7: Al2O3 / hexane / 24 h / 60 °C View Scheme

(1R,3S,5R)-3-<(1R)-1-Methyl-3-oxobutyl>-3,6,6-trimethylbicyclo<3.1.1>heptan-2-one (72453-41-9) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 2: Al2O3 / hexane / 24 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1: acetic acid; hydrogenchloride / 21 h / 20 °C / Inert atmosphere 2: acetic acid; sodium acetate / 2 h / 100 °C View Scheme

(1R,3R,5R)-6,6-Dimethyl-3-(1-hydroxyethyl)bicyclo<3.1.1>heptan-2-one (72453-38-4, 72541-05-0, 73068-69-6) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: 90 percent / p-toluenesulfonic acid / benzene / 2 h / Heating 2: 81 percent / TiCl4 / CH2Cl2 3: 71 percent / NaNH2 / benzene 4: 1.) O3; 2.) Zn/CH3COOH / 1.) -78 deg C, 30 min; 2.) room temperature overnight. 5: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 6: Al2O3 / hexane / 24 h / 60 °C View Scheme
Multi-step reaction with 6 steps 1: 90 percent / p-toluenesulfonic acid / benzene / 2 h / Heating 2: 89 percent / TiCl4 / CH2Cl2 / 2 h / -78 °C 3: 72 percent / NaNH2 / benzene / 1.) reflux, 5 h; 2.) 45 deg C, 17.5 h. 4: 1.) mercuric acetate; 2.) LiCl, PdCl2, CuCl2. / 1.) room temperature, CH3OH, 15 min; 2.) 55 deg C, CH3OH, 1 hour. 5: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 6: Al2O3 / hexane / 24 h / 60 °C View Scheme

(1R,5R)-6,6-Dimethyl-2-<(trimethylsilyl)oxy>bicyclo<3.1.1>hept-2-ene (72453-33-9) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 7 steps 1: 96 percent / TiCl4 / CH2Cl2 / 1.5 h / -78 °C 2: 90 percent / p-toluenesulfonic acid / benzene / 2 h / Heating 3: 81 percent / TiCl4 / CH2Cl2 4: 71 percent / NaNH2 / benzene 5: 1.) O3; 2.) Zn/CH3COOH / 1.) -78 deg C, 30 min; 2.) room temperature overnight. 6: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 7: Al2O3 / hexane / 24 h / 60 °C View Scheme
Multi-step reaction with 7 steps 1: 96 percent / TiCl4 / CH2Cl2 / 1.5 h / -78 °C 2: 90 percent / p-toluenesulfonic acid / benzene / 2 h / Heating 3: 89 percent / TiCl4 / CH2Cl2 / 2 h / -78 °C 4: 72 percent / NaNH2 / benzene / 1.) reflux, 5 h; 2.) 45 deg C, 17.5 h. 5: 1.) mercuric acetate; 2.) LiCl, PdCl2, CuCl2. / 1.) room temperature, CH3OH, 15 min; 2.) 55 deg C, CH3OH, 1 hour. 6: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 7: Al2O3 / hexane / 24 h / 60 °C View Scheme

(1R,3S,5S)-6,6-Dimethyl-3-<1-methyl-3-butenyl>bicyclo<3.1.1>heptan-2-one (72453-39-5, 72541-06-1, 73068-72-1, 73068-73-2, 75657-63-5) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 72 percent / NaNH2 / benzene / 1.) reflux, 5 h; 2.) 45 deg C, 17.5 h. 2: 1.) mercuric acetate; 2.) LiCl, PdCl2, CuCl2. / 1.) room temperature, CH3OH, 15 min; 2.) 55 deg C, CH3OH, 1 hour. 3: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 4: Al2O3 / hexane / 24 h / 60 °C View Scheme

(1R,3S,5S)-6,6-Dimethyl-3-<1-methyl-3-methyl-3-butenyl>bicyclo<3.1.1.>heptan-2-one (72453-42-0, 72541-07-2, 73068-70-9, 73068-71-0, 75657-65-7) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 71 percent / NaNH2 / benzene 2: 1.) O3; 2.) Zn/CH3COOH / 1.) -78 deg C, 30 min; 2.) room temperature overnight. 3: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 4: Al2O3 / hexane / 24 h / 60 °C View Scheme

(1R,3S,5R)-3-<1-Methyl-3-butenyl>-3,6,6-trimethylbicyclo<3.1.1>heptan-2-one (72453-40-8, 72521-66-5, 75657-64-6) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) mercuric acetate; 2.) LiCl, PdCl2, CuCl2. / 1.) room temperature, CH3OH, 15 min; 2.) 55 deg C, CH3OH, 1 hour. 2: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 3: Al2O3 / hexane / 24 h / 60 °C View Scheme

(1R,3S,5R)-3-<1-Methyl-3-methyl-3-butenyl>-3,6,6-trimethylbicyclo<3.1.1>heptan-2-one (72453-43-1, 72541-08-3, 75657-66-8) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) O3; 2.) Zn/CH3COOH / 1.) -78 deg C, 30 min; 2.) room temperature overnight. 2: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 3: Al2O3 / hexane / 24 h / 60 °C View Scheme

(1R,5R)-6,6-Dimethyl-3-(Z)-ethylidenebicyclo<3.1.1>heptan-2-one (73068-31-2) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: p-toluenesulfonic acid monohydrate / ethanol / 3 h / Ambient temperature 2: 81 percent / TiCl4 / CH2Cl2 3: 71 percent / NaNH2 / benzene 4: 1.) O3; 2.) Zn/CH3COOH / 1.) -78 deg C, 30 min; 2.) room temperature overnight. 5: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 6: Al2O3 / hexane / 24 h / 60 °C View Scheme
Multi-step reaction with 6 steps 1: p-toluenesulfonic acid monohydrate / ethanol / 3 h / Ambient temperature 2: 89 percent / TiCl4 / CH2Cl2 / 2 h / -78 °C 3: 72 percent / NaNH2 / benzene / 1.) reflux, 5 h; 2.) 45 deg C, 17.5 h. 4: 1.) mercuric acetate; 2.) LiCl, PdCl2, CuCl2. / 1.) room temperature, CH3OH, 15 min; 2.) 55 deg C, CH3OH, 1 hour. 5: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 6: Al2O3 / hexane / 24 h / 60 °C View Scheme

(1R,5R)-6,6-Dimethyl-3-(E)-ethylidenebicyclo<3.1.1>heptan-2-one (72453-37-3) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 81 percent / TiCl4 / CH2Cl2 2: 71 percent / NaNH2 / benzene 3: 1.) O3; 2.) Zn/CH3COOH / 1.) -78 deg C, 30 min; 2.) room temperature overnight. 4: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 5: Al2O3 / hexane / 24 h / 60 °C View Scheme
Multi-step reaction with 5 steps 1: 89 percent / TiCl4 / CH2Cl2 / 2 h / -78 °C 2: 72 percent / NaNH2 / benzene / 1.) reflux, 5 h; 2.) 45 deg C, 17.5 h. 3: 1.) mercuric acetate; 2.) LiCl, PdCl2, CuCl2. / 1.) room temperature, CH3OH, 15 min; 2.) 55 deg C, CH3OH, 1 hour. 4: 73 percent / HCl / acetic acid / 21 h / Ambient temperature 5: Al2O3 / hexane / 24 h / 60 °C View Scheme
Multi-step reaction with 6 steps 1.1: magnesium / tetrahydrofuran / 0.5 h / Reflux 1.2: -78 °C 2.1: potassium hydride; 18-crown-6 ether / tetrahydrofuran / 6 h / 0 °C / Inert atmosphere 3.1: sodium amide / benzene / 5 h / Inert atmosphere; Reflux 3.2: 17.5 h / 45 °C 4.1: acetic acid; zinc / dichloromethane / 5 h / -78 - 30 °C / Inert atmosphere 5.1: acetic acid; hydrogenchloride / 21 h / 20 °C / Inert atmosphere 6.1: acetic acid; sodium acetate / 2 h / 100 °C View Scheme

2-Methyl-4-isopropenyl-6-hydroxymethylen-cyclohexanon (67779-36-6) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: TsOH 2: (i) KOtBu, tBuOH, (ii) aq. KOH View Scheme

(+)-(2R,4R)-2-methyl-4-isopropenylcyclohexanone (118710-90-0) → (+)-nootkatone (4674-50-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaOMe, MeOH 2: TsOH 3: (i) KOtBu, tBuOH, (ii) aq. KOH View Scheme

(+)-nootkatone (4674-50-4) → 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2-ol (840474-83-1)

Conditions	Yield
With sodium tetrahydroborate In methanol at 0℃; for 4.33333h; Time;	98.3%

(+)-nootkatone (4674-50-4) → 6-isopropyl-4,4a-dimethyl-4a,5,6,7,8,8a-hexahydronaphthalen-2(1H)-one (5195-69-7)

Conditions	Yield
With Wilkinson's catalyst; hydrogen In benzene at 20℃; for 8h;	96%
With Wilkinson's catalyst; hydrogen In benzene for 14h; Ambient temperature;	81%
With Wilkinson's catalyst; hydrogen In benzene for 14h; Ambient temperature;	81%
With tris(triphenylphosphine)rhodium(l) chloride; hydrogen In benzene for 8h;
With Wilkinson's catalyst; hydrogen under 5250.53 Torr; for 2h;

(+)-nootkatone (4674-50-4) → 6-isopropenyl-4,4a-dimethyl-3,4,5,6,7,8-hexahydro-1aH-naphtho[1,8a-b]oxiren-2-one (439112-90-0)

Conditions	Yield
With dihydrogen peroxide; sodium hydroxide	96%

(+)-nootkatone (4674-50-4) + lithium tetramethyl alanate (14281-94-8, 32661-49-7, 32661-50-0) → (4R,4aS,6R)-6-Isopropenyl-2,4,4a-trimethyl-2,3,4,4a,5,6,7,8-octahydro-naphthalen-2-ol

Conditions	Yield
copper(I) bromide In tetrahydrofuran; diethyl ether 0.5 h at 0 deg C, 6 h at room temp.;	94%

(+)-nootkatone (4674-50-4) + acetylenemagnesium bromide (4301-14-8) → (3R,4aS,5R)-7-ethynyl-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5-hexahydronaphthalene (1449115-27-8)

Conditions	Yield
Stage #1: (+)-nootkatone With N,N-phenylbistrifluoromethane-sulfonimide; lithium hexamethyldisilazane at -78℃; Inert atmosphere; Stage #2: acetylenemagnesium bromide With tetrakis(triphenylphosphine) palladium(0) at 20℃; Inert atmosphere;	94%

(+)-nootkatone (4674-50-4) → fluoro-(+)-nootkatone

Conditions	Yield
With HO4S(1-)*K(1+)*13FH In 1,2-dichloro-ethane at 0 - 20℃; for 2h; regioselective reaction;	94%

(+)-nootkatone (4674-50-4) → (+)-cis-4,4a-dimethyl-4,4a,5,6,7,8-hexahydro-2-(3H)-naphthalenone (51557-49-4)

Conditions	Yield
Stage #1: (+)-nootkatone With methanol; ozone Stage #2: With ferrous(II) sulfate heptahydrate; thiophenol at -78 - 20℃; for 0.5h;	94%

(+)-nootkatone (4674-50-4) → 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2α-ol (50763-67-2)

Conditions	Yield
With sodium tetrahydroborate; cerium(III) chloride heptahydrate In methanol at 23℃; for 0.166667h; Inert atmosphere;	91%
With sodium tetrahydroborate; cerium(III) chloride	87%
With sodium tetrahydroborate; cerium(III) chloride In ethanol at 20℃; for 1h;	82.7%

(+)-nootkatone (4674-50-4) → C15H22Cl2

Conditions	Yield
With C26H24Cl2P2(2+)*CH2Cl2*2C2H4Cl2*Cl5Sb(2-); water In nitromethane at 23℃; for 16h; Inert atmosphere;	91%

trimethylaluminum (75-24-1) + (+)-nootkatone (4674-50-4) → (3R,4aS,5R)-3-Isopropenyl-4a,5,7-trimethyl-1,2,3,4,4a,5-hexahydro-naphthalene + (4R,4aS,6R)-6-Isopropenyl-4,4a,8a-trimethyl-octahydro-naphthalen-2-one

Conditions	Yield
copper(I) bromide In tetrahydrofuran for 22h; Ambient temperature;	A 90% B 2%
bis(acetylacetonate)nickel(II) In tetrahydrofuran for 4.5h; Ambient temperature;	A 17% B 77%

(+)-nootkatone (4674-50-4) + acetylenemagnesium bromide (4301-14-8)

Conditions	Yield
Stage #1: (+)-nootkatone With 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride at 20℃; Inert atmosphere; Stage #2: acetylenemagnesium bromide With tetrakis(triphenylphosphine) palladium(0) at 20℃; Inert atmosphere;	88%

Upstream product

• 10219-75-7 valencene 
• 20489-50-3 (4R,6R,10S)-4,10-dimethyl-6-(1‘-hydroxyisopropyl)-1-en-3,4,5,6,7,8-hexahydronaphthalen-2-one 
• 72453-44-2 (4R,4aS,6R)-4,4a,5,6,7,8-Hexahydro-4,4a-dimethyl-6-(1-chloro-1-methylethyl)-2(3H)-naphthalenone 
• 67779-29-7 2-Methyl-4-isopropenyl-6-n-butylthiomethylen-cyclohexanon 
• 3102-33-8 trans-3-penten-2-one 
• 6750-66-9 cis-2-Methyl-4-isopropenyl-cyclohexanon 
• 72453-43-1 3-(1,3-dimethylbut-3-enyl)-3,6,6-trimethylbicyclo[3.1.1]heptan-2-one 
• 18172-67-3 beta-pinene 
• 329309-57-1 (4R,4aS,6R)-2-hydroperoxy-4,4a-dimethyl-6-(prop-1-en-2-yl)-2,3,4,4a,5,6,7,8-octahydronaphthalene 
• 563-41-7 semicarbazide hydrochloride 
• 5090-61-9 (2R,8R,8aS)-8,8a-dimethyl-2-(prop-1-en-2-yl)-1,2,3,7,8,8a-hexahydronaphthalene 
• 20489-45-6 11-hydroxy-4α,5α,7β-eremophil-1(10)-ene 
• 118710-90-0 (2R,4R)-(-)-2-methyl-4-isopropenylcyclohexanone 
• 67779-36-6 2-Methyl-4-isopropenyl-6-hydroxymethylen-cyclohexanon 

Downstream Products

• 438536-22-2 nootkatone-11,12-epoxide 
• 27024-87-9 (4R,4aS,6R)-6-acetyl-4,4a-dimethyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one 
• 141695-83-2 (R)-3-((1S,5R)-2-Formyl-5-isopropenyl-1-methyl-cyclohex-2-enyl)-butyric acid 
• 141695-82-1 (1R,4R,6S,7R,9S,10S)-4-Isopropenyl-10-methoxy-6,7-dimethyl-11,12-dioxa-tricyclo[7.2.1.0^1,6]dodecan-9-ol 
• 141695-80-9 (2R,2aS,5R,5aS,7R,9aR)-2-((2S,4aS,5R)-4a,5-Dimethyl-7-oxo-1,2,3,4,4a,5,6,7-octahydro-naphthalen-2-yl)-7-isopropenyl-2,5,5a-trimethyl-octahydro-cyclobuta[d]naphthalen-3-one 
• 50763-67-2 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2α-ol 
• 50763-66-1 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2β-ol 
• 20489-54-7 tetrahydronootkatone 
• 840474-83-1 4α,4aα-dimethyl-6β-(1-methylethenyl)-2,3,4,4a,5,6,7,8-octahydronaphthalene-2-ol 
• 15764-04-2 (4R,4aS)-(+)-4,4a-dimethyl-6-isopropylidene-4,4a,5,6,7,8-hexahydro-(3H)-naphthalen-2-one 
• 226546-99-2 9α-hydroxy-2-oxo-4α,5α,7β-eremophila-1(10),11-diene 
• 226547-04-2 11,12-dihydroxy-2-oxo-4α,5α,7β-eremophila-1(10),11-diene 
• 114394-01-3 (11S)-nootkatone-11,12-diol 
• 114394-01-3 (11R)-nootkatone-11,12-diol 

Relevant articles and documents

Preparation of (-)-aristolochene from (+)-valencene: Absolute configuration of (+)-aristolochene from Aspergillus terreus

The absolute configuration of (+)-aristolochene (1a), isolated from Aspergillus terreus, has been established by direct comparison with a sample of (-)-aristolochene (1b) prepared from (+)-valencene (2).

Highly efficient production of nootkatone, the grapefruit aroma from valencene, by biotransformation

Nootkatone (2), the most important and expensive aromatic of grapefruit, decreases the somatic fat ratio, and thus its demand is increasing in the cosmetic and fiber sectors. A sesquiterpene hydrocarbon, (+)-valencene (1), which is cheaply obtained from Valencia orange, was biotransformed by the green algae Chlorella species and fungi such as Mucor species, Botryosphaeria dothidea, and Botryodiplodia theobromae to afford nootkatone (2) in high yield.

Manganese complex catalyst for valencene oxidation: The first use of metalloporphyrins for the selective production of nootkatone

This work describes the oxidation of valencene, a sesquiterpene easily obtained from citrus fruits, and responsible for the fresh odor of oranges. The reactions were catalyzed by manganese porphyrins derived from 5,10,15,20-tetrakis(3,5-dimethoxyphenyl)porphyrin (H2T3,5DMPP): [MnIII(T3,5DMPP)Cl] (MnP1) and [MnIII(Br12T3,5DMPP)Cl] (MnP2), using iodosylbenzene (PhIO), iodobenzene diacetate [PhI(OAc)2], and molecular oxygen as oxidants. The systems MnP1/O2/acetonitrile and MnP1/O2/diethyl carbonate led to higher yields of valencene oxidation products (44% and 48%, respectively) as compared with MnP2 (9% and 7%, respectively), with nootkatone being the major product. The addition of a small amount of imidazole (molar MnP1: imidazole ratio of 1:5) to the MnP1/O2/diethyl carbonate led to superior yields (64%) as compared with systems without the additive. A mechanism for the formation of the two products obtained was also proposed.

METHOD FOR THE MANUFACTURE OF α,β-UNSATURATED KETONES

A method for the manufacture of an α,β-unsaturated ketone, which method comprises oxidizing an alkene having -CH2- adjacent a carbon-carbon double bond to α,β-unsaturated ketone by passing air or oxygen through a solution of the hydrocarbon containing a catalyst consisting of N-hydroxyphthalimide (NHPI) and cobalt diacetate tetrahydrate at standard temperature and pressure during a period of at least 12 hours.

PROCESS FOR THE PREPARATION OF NOOTKATONE BY USING A IRON (III) PORPHYRIN COMPLEX CATALYST

An allylic oxidation process comprising: forming a mixture containing valencene and an iron (lll)-X porphyrin complex catalyst in a sustainable solvent, introducing molecular oxygen into the mixture, and effecting allylic oxidation to produce nootkatone.