499-44-5

Hazards Identification

Pictogram(s):

Signal:

Warning

GHS Hazard Statements:

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

Precautionary Statement Codes:

P264, P270, P301+P317, P330, and P501

Hazard Classes and Categories:

Acute Tox. 4 (100%)

Usage

Uses

Used in Antimicrobial Applications:
Hinokitiol is used as an antimicrobial agent for its inhibitory effects on various microorganisms, including Chlamydia trachomatis. This makes it potentially useful as a topical drug in the medical field.
Used in Food Industry:
Hinokitiol is used as an antibacterial additive in the food industry to maintain freshness and prevent spoilage, ensuring the safety and quality of the products.
Used in Cosmetics:
In the cosmetics industry, Hinokitiol is utilized for its antimicrobial and preservative properties, helping to extend the shelf life and maintain the integrity of cosmetic products.
Used in Oral Care:
Hinokitiol is used in oral care products, such as toothpaste, due to its antibacterial properties, which help maintain oral hygiene and prevent dental issues.
Used in Skin Care:
Hinokitiol is used in skin care products for its antimicrobial and preservative properties, promoting skin health and preventing the growth of harmful microorganisms on the skin.
Used in Eye Care:
Hinokitiol is used in eye drops for its antimicrobial properties, helping to maintain eye health and prevent infections.
Used in Japan as a Food Additive:
Hinokitiol is also used as a food additive in Japan, where it is recognized for its antimicrobial and preservative qualities, contributing to the safety and longevity of the products.

benefits

Hinokitiol (β-thujaplicin) is a naturally occurring antioxidant, found in the heartwood of certain plants. It acts as a metal chelator and, also, enhances the activity of superoxide dismutase (Huang et al., 2015). It was found to be very protective in the assay. It has not been previously studied as a HC protectant. In addition to its antioxidant properties, hinokitiol has been shown to reduce inflammation via suppression of NFκB, and metalloproteinases, and to activate caspase 3. The former activities could contribute to its protective effect.Hinokitiol is a superpower ingredient that has anti-inflammatory, antioxidant, antibacterial, anti-fungal and anti-melanogenic properties. Best of all, hinokitiol is as gentle as it is powerful. Hinokitiol’s properties allow it to target the inflammatory redness and blemishes seen in rosacea and acne. Hinokitiol is effective against P. acnes bacteria, and there is no known acquired resistance to it, unlike other prescription antibiotics.

Safety

The safety of hinokitiol has been tested in rats and no carcinogenic effect to rats was found.In 2006, hinokitiol was categorized under the Domestic substances list (DSL) in Canada as non-persistent, non-bioaccumulative and non-toxic to aquatic organisms.

Anticancer Research

Studied in xenograft tumors such lung adenocarcinoma cell, EGFR-TKI-resistantlines PC9-IR and H1975 in which the growth inhibition was observed, a novel antitumormechanism was hypothesized. In summary, the hinokitiol can induce DNAdamage and autophagy (Rodrigues et al. 2015).

References

1) Ido et al (1999) Induction of apoptosis by hinokitiol, a potent iron chelator, in teratocarcinoma F9 cells is mediated through the activation of caspase-3; Cell Prolif., 32 63 2) Suzuki et al. (2000) Hinokitiol, a selective inhibitor of the platelet-type isozyme of arachidonate 12-lipoxygenase; Biochem. Biophys. Res. Commun., 275 885 3) Morita et al. (2007) The mechanism of the bactericidal activity of hinokitiol; Biocontrol Sci., 12 101 4) Liu and Yamauchi (2006) Hinokitiol, a metal chelator derived from natural plants, suppresses cell growth and disrupts androgen receptor signaling in prostate carcinoma cell lines; Biochem. Biophys. Res. Commun., 351 26 5) Lee et al. (2010) Hinokitiol activates the hypoxia-inducible factor (HIF) pathway through inhibition of HIF hydroxylases; Biochem. Biophys. Res. Commun., 396 370

InChI:InChI=1/C10H12O2/c1-7(2)8-4-3-5-9(11)10(12)6-8/h3-7H,1-2H3,(H,11,12)

Synthetic route

2-amino-6-isopropyl-cycloheptatrienone (55076-49-8) → hinokitiol (499-44-5)

Conditions	Yield
With potassium hydroxide	100%

β-dolabrin (4570-11-0) → hinokitiol (499-44-5)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethanol at 22℃; under 760 Torr; for 6.5h;	98%
With hydrogen; palladium on activated charcoal In ethanol	98%

isopropanol boric acid (52732-22-6) + 2-hydroxy-4-chloro-2,4,6-cycloheptatrien-1-one (698-48-6) → hinokitiol (499-44-5)

Conditions	Yield
With potassium phosphate In tetrahydrofuran at 100℃; for 2h;	97.5%

(5S)-6-isopropyl-3-cycloheptene-1,2-dione (310905-95-4) → hinokitiol (499-44-5)

Conditions	Yield
Stage #1: (5S)-6-isopropyl-3-cycloheptene-1,2-dione With pyrrolidone hydrotribromide In tetrahydrofuran at 20℃; for 1h; Bromination; Stage #2: With lithium carbonate; lithium bromide In N,N-dimethyl-formamide for 2h; Aromatisation; Heating;	71%

4-bromo-2-hydroxycycklohepta-2,4,6-trien-1-one (698-47-5) + isopropenyltrimethylstannane (3043-46-7) → hinokitiol (499-44-5)

Conditions	Yield
Stage #1: 4-bromo-2-hydroxycycklohepta-2,4,6-trien-1-one; isopropenyltrimethylstannane With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane for 1h; Reflux; Stage #2: With 5%-palladium/activated carbon; hydrogen In ethanol at 20℃; under 760.051 Torr; for 24h;	53%

4-isopropyl-cycloheptanone (13656-84-3) → hinokitiol (499-44-5)

Conditions	Yield
With selenium(IV) oxide; ethanol Erwaermen des Reaktionsprodukts mit N-Brom-succinimid in CHCl3;

4-isopropyl-cycloheptanone (13656-84-3) → hinokitiol (499-44-5) + 3-bromo-5-isopropyl-tropolone (2891-67-0)

Conditions	Yield
With selenium(IV) oxide; ethanol Behandeln des Reaktionsprodukts mit Brom in Essigsaeure und Erhitzen des hierbei erhaltenen Reaktionsprodukts mit Wasserdampf;

3-isopropylcycloheptanone (108168-72-5) → hinokitiol (499-44-5)

Conditions	Yield
With selenium(IV) oxide; ethanol Erwaermen des Reaktionsprodukts mit N-Brom-succinimid in CHCl3;
Multi-step reaction with 2 steps 1: selenium dioxide / ethanol; H2O / 2 h / 90 °C 2: 1.) phenyltrimethylammonium tribromide 2.) LiCl, Li2CO3 / 1.) THF, RT, 1.75 h, 2.) DMF, 120 deg C, 45 min View Scheme

(1S,5R)-7,7-Dichloro-1-isopropyl-bicyclo[3.2.0]hept-2-en-6-one → hinokitiol (499-44-5)

Conditions	Yield
With potassium acetate

(1R,5S)-7,7-Dichloro-3-isopropyl-bicyclo[3.2.0]hept-2-en-6-one → hinokitiol (499-44-5)

Conditions	Yield
With potassium acetate

2-hydroxy-6-isopropyl-2,4,6-cycloheptatrien-1-one (499-44-5) → (Z)-Cyclooctene (931-88-4, 931-87-3) + hinokitiol (499-44-5)

Conditions	Yield
In decalin at 180℃; for 4h;	A 95 % Spectr. B n/a

2-hydroxy-6-isopropyl-2,4,6-cycloheptatrien-1-one (499-44-5) → hinokitiol (499-44-5) + cyclopentene (142-29-0)

Conditions	Yield
In decalin at 180℃; for 3h;	A n/a B 95 % Spectr.

4-isopropylcycloheptane-1,2-dione (108168-73-6) → hinokitiol (499-44-5)

Conditions	Yield
With C6H5N(1+); lithium chloride Yield given. Multistep reaction;
With phenyltrimethylammonium tribromide; lithium carbonate; lithium chloride 1.) THF, RT, 1.75 h, 2.) DMF, 120 deg C, 45 min; Yield given. Multistep reaction;

2-chloro-6-isopropyl-cycloheptatrienone (66967-15-5) → hinokitiol (499-44-5)

Conditions	Yield
With phosphoric acid; acetic acid

2-chloro-5-isopropyltropone (66967-10-0) → hinokitiol (499-44-5)

Conditions	Yield
With phosphoric acid; acetic acid Heating;

/PBWLC126-1000/ → hinokitiol (499-44-5)

Conditions	Yield
oxidation;

(R)-3-(1-methylethyl)-6-oxoheptanal dimethylacetal (105897-85-6) → hinokitiol (499-44-5) + 2-bromoprop-2-enyl halide

Conditions

Yield

Multi-step reaction with 7 steps 1.1: n-BuLi; diisopropylamine / tetrahydrofuran; hexane / 0.5 h / -15 - 0 °C 1.2: tetrahydrofuran; hexane / 2 h / -78 - 20 °C 2.1: TiCl4 / CH2Cl2 / 0.17 h / -78 °C 3.1: 63 percent / p-TsOH; 4 Angstroem molecular sieves / benzene / 1 h / Heating 4.1: n-BuLi; diisopropylamine / tetrahydrofuran; hexane / 0.5 h / -15 - 0 °C 4.2: tetrahydrofuran; hexane / 0.5 h / -15 - 20 °C 5.1: MCPBA / hexane / 4 h / 20 °C 5.2: 0.8 g / Et3N*3HF / CH2Cl2 / 2 h / 20 °C 6.1: 88 percent / Dess-Martin periodinane / CH2Cl2 / 1 h / 20 °C 7.1: pyrrolidone hydrotribromide / tetrahydrofuran / 1 h / 20 °C 7.2: 71 percent / LiBr; Li2CO3 / dimethylformamide / 2 h / Heating View Scheme

(5R)-5-isopropyl-2-cyclohepten-1-one (310905-92-1) → hinokitiol (499-44-5) + 2-bromoprop-2-enyl halide

Conditions

Yield

Multi-step reaction with 4 steps 1.1: n-BuLi; diisopropylamine / tetrahydrofuran; hexane / 0.5 h / -15 - 0 °C 1.2: tetrahydrofuran; hexane / 0.5 h / -15 - 20 °C 2.1: MCPBA / hexane / 4 h / 20 °C 2.2: 0.8 g / Et3N*3HF / CH2Cl2 / 2 h / 20 °C 3.1: 88 percent / Dess-Martin periodinane / CH2Cl2 / 1 h / 20 °C 4.1: pyrrolidone hydrotribromide / tetrahydrofuran / 1 h / 20 °C 4.2: 71 percent / LiBr; Li2CO3 / dimethylformamide / 2 h / Heating View Scheme

(5S)-7-hydroxy-5-isopropyl-2-cyclohepten-1-one (310905-94-3) → hinokitiol (499-44-5) + 2-bromoprop-2-enyl halide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 88 percent / Dess-Martin periodinane / CH2Cl2 / 1 h / 20 °C 2.1: pyrrolidone hydrotribromide / tetrahydrofuran / 1 h / 20 °C 2.2: 71 percent / LiBr; Li2CO3 / dimethylformamide / 2 h / Heating View Scheme

(5R)-5-isopropyl-3-methoxycycloheptanone (310905-91-0) → hinokitiol (499-44-5) + 2-bromoprop-2-enyl halide

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 63 percent / p-TsOH; 4 Angstroem molecular sieves / benzene / 1 h / Heating 2.1: n-BuLi; diisopropylamine / tetrahydrofuran; hexane / 0.5 h / -15 - 0 °C 2.2: tetrahydrofuran; hexane / 0.5 h / -15 - 20 °C 3.1: MCPBA / hexane / 4 h / 20 °C 3.2: 0.8 g / Et3N*3HF / CH2Cl2 / 2 h / 20 °C 4.1: 88 percent / Dess-Martin periodinane / CH2Cl2 / 1 h / 20 °C 5.1: pyrrolidone hydrotribromide / tetrahydrofuran / 1 h / 20 °C 5.2: 71 percent / LiBr; Li2CO3 / dimethylformamide / 2 h / Heating View Scheme

((S)-4-Isopropyl-cyclohepta-1,6-dienyloxy)-trimethyl-silane (310905-93-2) → hinokitiol (499-44-5) + 2-bromoprop-2-enyl halide

Conditions	Yield
Multi-step reaction with 3 steps 1.1: MCPBA / hexane / 4 h / 20 °C 1.2: 0.8 g / Et3N*3HF / CH2Cl2 / 2 h / 20 °C 2.1: 88 percent / Dess-Martin periodinane / CH2Cl2 / 1 h / 20 °C 3.1: pyrrolidone hydrotribromide / tetrahydrofuran / 1 h / 20 °C 3.2: 71 percent / LiBr; Li2CO3 / dimethylformamide / 2 h / Heating View Scheme

[(R)-4-(2,2-Dimethoxy-ethyl)-5-methyl-1-methylene-hexyloxy]-trimethyl-silane (310905-90-9) → hinokitiol (499-44-5) + 2-bromoprop-2-enyl halide

Conditions

Yield

Multi-step reaction with 6 steps 1.1: TiCl4 / CH2Cl2 / 0.17 h / -78 °C 2.1: 63 percent / p-TsOH; 4 Angstroem molecular sieves / benzene / 1 h / Heating 3.1: n-BuLi; diisopropylamine / tetrahydrofuran; hexane / 0.5 h / -15 - 0 °C 3.2: tetrahydrofuran; hexane / 0.5 h / -15 - 20 °C 4.1: MCPBA / hexane / 4 h / 20 °C 4.2: 0.8 g / Et3N*3HF / CH2Cl2 / 2 h / 20 °C 5.1: 88 percent / Dess-Martin periodinane / CH2Cl2 / 1 h / 20 °C 6.1: pyrrolidone hydrotribromide / tetrahydrofuran / 1 h / 20 °C 6.2: 71 percent / LiBr; Li2CO3 / dimethylformamide / 2 h / Heating View Scheme

4-bromo-2-hydroxycycklohepta-2,4,6-trien-1-one (698-47-5) → hinokitiol (499-44-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 54 percent / dichlorobis(triphenylphosphine)palladium(II) / dioxane / 1.3 h / Heating 2: 98 percent / hydrogen / 5percent Pd/C / ethanol View Scheme
Multi-step reaction with 2 steps 1: 54 percent / dichlorobis(triphenylphosphine)palladium(II) / dioxane / 1.33 h / Heating 2: 98 percent / H2 / 5percent Pd/C / ethanol / 6.5 h / 22 °C / 760 Torr View Scheme

3-Methoxycyclohepta-1,3,5-triene (1714-40-5) → hinokitiol (499-44-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: Et4NOTs / dimethylformamide / electroreduction 2: 1.) pyridinium bromide perbromide 2.) LiCl/LiCO3 / 2.) DMF 3: 100 percent / NH2NH2 4: 100 percent / KOH View Scheme
Multi-step reaction with 5 steps 1: Et4NOTs / dimethylformamide / electroreduction 2: 87 percent / aq. H2SO4 / tetrahydrofuran 3: 82 percent / 30percent H2O2/NaOH 4: 72 percent / aq. HCl 5: 1.) C6H5N(1+) 2.) LiCl/LiCO3 View Scheme

1-methoxycyclohepta-1,3,5-triene (1728-32-1) → hinokitiol (499-44-5)

Conditions	Yield
Multi-step reaction with 4 steps 2: 1.) pyridinium bromide perbromide 2.) LiCl/LiCO3 / 2.) DMF 3: 100 percent / NH2NH2 4: 100 percent / KOH View Scheme
Multi-step reaction with 5 steps 2: 87 percent / aq. H2SO4 / tetrahydrofuran 3: 82 percent / 30percent H2O2/NaOH 4: 72 percent / aq. HCl 5: 1.) C6H5N(1+) 2.) LiCl/LiCO3 View Scheme
Multi-step reaction with 4 steps 1: Et4NOTs / dimethylformamide / electroreduction 2: 1.) pyridinium bromide perbromide 2.) LiCl/LiCO3 / 2.) DMF 3: 100 percent / NH2NH2 4: 100 percent / KOH View Scheme
Multi-step reaction with 5 steps 1: Et4NOTs / dimethylformamide / electroreduction 2: 87 percent / aq. H2SO4 / tetrahydrofuran 3: 82 percent / 30percent H2O2/NaOH 4: 72 percent / aq. HCl 5: 1.) C6H5N(1+) 2.) LiCl/LiCO3 View Scheme

β-isopropyltropolone (35193-01-2) → hinokitiol (499-44-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / NH2NH2 2: 100 percent / KOH View Scheme

6-Isopropyl-cyclohept-3-enone → hinokitiol (499-44-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 82 percent / 30percent H2O2/NaOH 2: 72 percent / aq. HCl 3: 1.) C6H5N(1+) 2.) LiCl/LiCO3 View Scheme

1-methoxy-6-isopropyl-1,3-cycloheptadiene (133826-10-5) → hinokitiol (499-44-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) pyridinium bromide perbromide 2.) LiCl/LiCO3 / 2.) DMF 2: 100 percent / NH2NH2 3: 100 percent / KOH View Scheme
Multi-step reaction with 4 steps 1: 87 percent / aq. H2SO4 / tetrahydrofuran 2: 82 percent / 30percent H2O2/NaOH 3: 72 percent / aq. HCl 4: 1.) C6H5N(1+) 2.) LiCl/LiCO3 View Scheme

4-Isopropyl-8-oxa-bicyclo[5.1.0]octan-2-one → hinokitiol (499-44-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 72 percent / aq. HCl 2: 1.) C6H5N(1+) 2.) LiCl/LiCO3 View Scheme

hinokitiol (499-44-5) → 2-hydroxy-7-iodo-4-isopropyltropone (32659-57-7)

Conditions	Yield
With sulfuric acid; iodine; potassium carbonate In chloroform	100%
With iodine; potassium carbonate In diethyl ether for 24h; Ambient temperature;	100%
With iodine	70%

piperazine (110-85-0) + formaldehyd (50-00-0) + hinokitiol (499-44-5) → 1,4-bis(6-hydroxy-4-isopropyl-7-oxo-1,3,5-cycloheptatrienylmethyl)piperazine (1211884-65-9)

Conditions	Yield
Stage #1: piperazine; formaldehyd; hinokitiol With acetic acid In methanol at 60℃; Mannich reaction; Stage #2: With sodium hydrogencarbonate In methanol; water	100%

formaldehyd (50-00-0) + 4-ethoxycarbonylpiperazine (120-43-4) + hinokitiol (499-44-5) → 4-(6-hydroxy-4-isopropyl-7-oxo-1,3,5-cycloheptatrienylmethyl)-1-piperazinecarboxylic acid ethyl ester (1211884-44-4)

Conditions	Yield
Stage #1: formaldehyd; 4-ethoxycarbonylpiperazine; hinokitiol With acetic acid In methanol at 60℃; Mannich reaction; Stage #2: With sodium hydrogencarbonate In methanol; water	99%

formaldehyd (50-00-0) + hinokitiol (499-44-5) + (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (122003-27-4) → 1-[N-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ylcarbonyl)]-4-(6-hydroxy-4-isopropyl-7-oxo-1,3,5-cycloheptatrienylmethyl)piperazine (1211884-55-7)

Conditions	Yield
Stage #1: formaldehyd; hinokitiol; (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone With acetic acid In methanol at 60℃; Mannich reaction; Stage #2: With sodium hydrogencarbonate In methanol; water	99%

hinokitiol (499-44-5) + methyl iodide (74-88-4) → 4-isopropyltropolone methyl ether (18448-52-7)

Conditions	Yield
With perhydrodibenzo-18-crown-6; potassium carbonate In acetonitrile for 10h; Heating;	96.4%

hinokitiol (499-44-5) + trifluoroborane diethyl ether (109-63-7) → difluoro(3-isopropyl-7-oxo-1,3,5-cycloheptatrienyloxy)borane (2248-50-2)

Conditions	Yield
In not given react. hinokitiol and boron trifluoride etherate; product recrystd. from chloroform-benzene (4:7);	96%

hinokitiol (499-44-5) + p-toluenesulfonyl chloride (98-59-9) → 4-(1-methylethyl)-2-[[(4-methylphenyl)sulfonyl]oxy]-2,4,6-cycloheptatrien-1-one (69141-46-4)

Conditions	Yield
In pyridine	96%

hinokitiol (499-44-5) + OsHCl(CO)(P(p-tolyl)3)3 → C53H54O3OsP2

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In benzene for 2.5h; Reflux; Inert atmosphere;	95%

indium chloride + hinokitiol (499-44-5) → trans-{tris(4-iso-propyl-2-hydroxy-2,4,6-cycloheptatrien-1-onato-O,O')-indium(III)} (154727-99-8, 16973-43-6)

Conditions	Yield
In ethanol refluxed; 1 h; left to stand for 48 h;; pptd. from H2O; crystd. after 48 h; washed with EtOH/H2O; dried over CaCl2; elem. anal.;;	91%

hydridocarbonylchlorotris(triphenylphosphine)osmium(II) (16971-31-6, 36007-23-5) + hinokitiol (499-44-5) → C47H42O3OsP2

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In benzene for 5.5h; Reflux; Inert atmosphere;	91%

morpholine (110-91-8) + formaldehyd (50-00-0) + hinokitiol (499-44-5) → 4-(4-isopropyl-6-hydroxy-7-oxo-1,3,5-cycloheptatrienylmethyl)morpholine

Conditions	Yield
With acetic acid In methanol at 60℃; Mannich reaction;	88%

(carbonyl)(chloro)(hydrido)tris(triphenylphosphine)ruthenium(II) (157072-60-1, 61521-25-3, 166941-05-5, 16971-33-8) + hinokitiol (499-44-5) → C47H42O3P2Ru

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In benzene for 2.5h; Reflux; Inert atmosphere;	88%

Iron(III) nitrate nonahydrate + hinokitiol (499-44-5) → tris(4-isopropyltropolonato)iron(III) (31396-80-2)

Conditions	Yield
In methanol; ethanol to soln. of iron salt in MeOH was added to soln. of hinokitiol in MeOH, stirred for 1 h at room temp.; filtered, washed with EtOH, Et2O, dried in vac. for 2 h;	87.6%
In ethanol at 20℃; for 2h;	86.7%

copper(ll) sulfate pentahydrate + hinokitiol (499-44-5) → [Cu(II)(4-isopropyltropolone)2] C20H22CuO4, monoclinic, P21/N (14076-63-2, 685836-60-6)

Conditions	Yield
In ethanol; water to soln. of ligand in 1:1 mixt. EtOH and water (20 ml) was added CuSO4, soln. was refluxed for 2 h; soln. was passed through folded filter paper, filtrate was evapd. slowlyat room temp., after few days crystals were grown, ppt. collected, wash ed with H2O, dried in vac.; elem. anal.;	76.5%

hinokitiol (499-44-5) + 3,4,5-Trimethoxybenzoyl chloride (4521-61-3) → 3,4,5-trimethoxy-benzoic acid 3-isopropyl-7-oxo-cyclohepta-1,3,5-trienyl ester

Conditions	Yield
With pyridine In dichloromethane for 12h; Heating;	76%

hinokitiol (499-44-5) + titanium tetrachloride (7550-45-0) → [Ti(hinokitiol)2Cl2] (1106674-51-4)

Conditions	Yield
In methanol; diethyl ether to soln. of TiCl4 in ether was added soln. of hinokitiol in ether, stirred for 2 h at room temp.; filtered, washed with ether, dried in vac. for 2 h;	74.1%

4-methoxybenzaldehyde diethylacetal (2403-58-9) + hinokitiol (499-44-5) → 3-(α-ethoxy-4-methoxybenzyl)-6-isopropyltropolone (92832-11-6)

Conditions	Yield
In toluene for 20h; Heating;	72%

6-hydroxy-2,5,7,8-tetramethyl-N-(2-piperazinoethyl)-2-chromanecarboxamide (313988-88-4) + formaldehyd (50-00-0) + hinokitiol (499-44-5) → 1-[N-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ylcarbonyl)ethylamino]-4-(6-hydroxy-4-isopropyl-7-oxo-1,3,5-cycloheptatrienylmethyl)piperazine (1211884-59-1)

Conditions	Yield
Stage #1: 6-hydroxy-2,5,7,8-tetramethyl-N-(2-piperazinoethyl)-2-chromanecarboxamide; formaldehyd; hinokitiol With acetic acid In methanol at 60℃; Mannich reaction; Stage #2: With sodium hydrogencarbonate In methanol; water	71%

tris(triphenylphosphine)ruthenium(II) chloride (15529-49-4, 41756-81-4) + hinokitiol (499-44-5) → C56H52O4P2Ru

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol for 1.5h; Inert atmosphere; Reflux;	71%

copper(ll) sulfate pentahydrate + hinokitiol (499-44-5) → [Cu(II)(4-isopropyltropolone)2]

Conditions	Yield
In ethanol; water to soln. of ligand in 1:1 mixt. EtOH and water (30 ml) was added CuSO4, soln. was refluxed for 2 h; soln. was passed through folded filter paper, filtrate was evapd. slowlyat room temp., after few days crystals were grown, ppt. collected, wash ed with H2O, dried in vac.; elem. anal.;	70.7%

1-ethoxyisochromane (75802-22-1) + hinokitiol (499-44-5) → 3-(1-isochromanyl)-6-isopropyltropolone (87864-22-0)

Conditions	Yield
at 150 - 160℃; for 6h;	66%
heating;

hinokitiol (499-44-5) + 4-methoxy-benzoyl chloride (100-07-2) → 4-methoxy-benzoic acid 3-isopropyl-7-oxo-cyclohepta-1,3,5-trienyl ester

Conditions	Yield
With pyridine In dichloromethane for 12h; Heating;	65%

hinokitiol (499-44-5) + antimony(III) bromide (7789-61-9) → [Sb(III)(hinokitiol)2Br]

Conditions	Yield
In methanol; benzene to soln. of SbBr3 in C6H6 was added soln. of hinokitiol in MeOH, stirredfor 2 h; filtered, evapd. in vac. at 30°C, dissolved in EtOH, filtered, filtrate slow evapd. at room temp., filtered, washed with cold EtOH, driedin vac. for 2 h;	62.5%

tin(II) chloride dihdyrate (10025-69-1) + hinokitiol (499-44-5) → Sn(hinokitiol)2 (58528-20-4)

Conditions	Yield
In ethanol; water a soln. of hydroxyketone in ethanol was added a stirred soln. of Sn-compound in water under N2, the soln. was stirred for 1.5 h; filtered, ppt. was dried under vac.; elem. anal.;	56%

1,1-diethoxy-but-2-ene (10602-34-3) + hinokitiol (499-44-5) → 3-isopropyl-6-(1-ethoxy-2-butenyl)tropolone (92397-04-1)

Conditions	Yield
at 160℃; for 5h;	55%

formaldehyd (50-00-0) + hinokitiol (499-44-5) + 1-(3,4-dimethoxybenzoyl)piperazine → 7-[4-(3-(3,4-dimethoxybenzoyl)piperazin-1-yl)methyl]-2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one

Conditions	Yield
With acetic acid In methanol at 60℃;	55%

Upstream product

• 10599-59-4 2-isopropylfuran 
• 35071-52-4 7,7-dichloro-3-isopropylbicyclo[3.2.0]hept-2-ene-6-one 
• 542-92-7 cyclopenta-1,3-diene 
• 13656-84-3 4-isopropyl-cycloheptanone 
• 108168-72-5 3-isopropylcycloheptanone 
• 55076-49-8 2-amino-6-isopropyl-cycloheptatrienone 
• 108168-73-6 4-isopropylcycloheptane-1,2-dione 
• 35193-01-2 β-isopropyltropolone 
• 698-47-5 4-bromo-2-hydroxycycklohepta-2,4,6-trien-1-one 
• 3043-46-7 isopropenyltrimethylstannane 
• 110-83-8 cyclohexene 
• 2415-79-4 7,7-dibromonorcarane 
• 310905-93-2 ((S)-4-Isopropyl-cyclohepta-1,6-dienyloxy)-trimethyl-silane 
• 310905-91-0 (5R)-5-isopropyl-3-methoxycycloheptanone 

Downstream Products

• 931-88-4 cis-Cyclooctene 
• 142-29-0 cyclopentene 
• 55076-49-8 2-amino-6-isopropyl-cycloheptatrienone 
• 103028-78-0 2-amino-4-isopropyl-cycloheptatrienone 
• 108973-66-6 2-benzylamino-6-isopropyl-cycloheptatrienone 
• 108975-97-9 2-benzylamino-4-isopropyl-cycloheptatrienone 
• 32659-57-7 6-isopropyl-3-iodo-tropolone 
• 6688-76-2 3,5-dibromo-6-isopropyl-tropolone 
• 92832-17-2 α,α-bis(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxytoluene 
• 92832-11-6 3-(α-ethoxy-4-methoxybenzyl)-6-isopropyltropolone 
• 101403-51-4 C₂₈H₃₀O₅ 
• 92832-15-0 α,α-bis(2-hydroxy-6-isopropyl-tropon-3yl)-4-chlorotoluene 
• 92397-08-5 α,α-bis(7-hydroxy-5-isopropyltropon-2-yl)-3-methoxytoluene 
• 101403-63-8 C₃₀H₃₄O₇ 

Relevant academic research and scientific papers

Method for preparing hinokitiol

The invention discloses a method for preparing hinokitiol. The method includes the steps of conducting an addition reaction on bromoform and an initial raw material compound, namely cyclohexene, to obtain a first compound, namely 7,7-dibromo bicyclo[4.1.0]heptane; the first compound is subjected to an oxidization reaction to obtain a second compound, namely 3,7,7-tribromo bicyclo[4.1.0]heptyl-2-ketone; the second compound is subjected to a substitution reaction to obtain a third compound, namely 7,7-dibromo-3-hydroxy bicyclo[4.1.0] heptyl-3-alkene-2-ketone; the third compound is subjected to aring enlargement reaction to obtain a fourth compound, namely 4-bromo-2-hydroxy cycloheptyl-2,4,6-triene-1-ketone; the fourth compound is subjected to an alkylation reaction to obtain hinokitiol.

A high-purity chinese juniper methyl alcohol of preparation method (by machine translation)

The invention discloses a method for preparing high-purity chinese juniper methyl alcohol, cyclopentadiene activated reagent after activation with isopropyl bromine instead should be containing various isomers of the isopropyl cyclopentadiene, then in the isomer conversion catalyst under the action of the isomerization reaction to obtain 1 - isopropyl cyclopentadiene; 1 - isopropyl cyclopentadiene and [...] react 1 - isopropyl cyclopentadiene and 4, 4 - [...] 5 - one; 1 - isopropyl cyclopentadiene and 4, 4 - [...] 5 - ketone with triethylamine heating reflux generating ring enlargement reaction to obtain the target product chinese juniper methyl alcohol. The invention raw materials used are cheap and easily obtained, and the step A through the isomer of a hydrocarbon conversion catalyst in use significantly reduces the by-product 2 - isopropyl cyclopentadiene and 5 - isopropyl cyclopentadiene generation, improves the yield of products, and Ru (Ac)3 - ZSM - 5 can be repeatedly used for four times still maintains good catalytic activity; step B by adjusting reaction solution in glacial acetic acid, effectively prevent the emergence of the diketone by-product. (by machine translation)

Preparation method of beta-thujaplicine

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of beta-thujaplicine. The preparation method comprises the steps that tri-n-propylamine, glacial acetic acid and water serve as reaction reagents, and a ring enlargement reaction occurs by 7,7-dichloro-3-isopropylbicycle[3.2.0]heptyl-2-ene-6-one (the compound structure is shown in formula 2).

Method for preparing high-purity hinokitiol and coordination complex thereof

The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and relates to a method for preparing high-purity hinokitiol and a coordination complex thereof. The method comprises the steps that 1-perchlorocyclopentadiene is generated by using cyclopentadiene, sodium hydroxide and NCS and reacts with dichloracetyl chloride, barium hydroxide is added, dilute sulphuric acid and chloroform are added after the reaction, and 1-chloro cyclopentadiene 4,4-dichloro cyclobutyl5-ketone is obtained through a final reaction; 1-chloro cyclopentadiene 4,4-dichloro cyclobutyl5-ketone is mixed with a mixed solution of acetic acid, acetone and water, then barium hydroxide is added, and 2-hydroxyl-4-chloro-2,4,6-cycloheptatrien-1-ketone is obtained through a final reaction; 2-hydroxyl-4-chloro-2,4,6-cycloheptatrien-1-ketone is added to THF, potassium phosphate and isopropylboronic acid are added, and the mixture after the reaction is added to a mixed solution of methanol, HCl/1 and 4-dioxane to obtain hinokitiol at last. The method has the advantages that the process is simple, the cost is low, and the product purity is high.

SUBSTITUTED TROPOLONE DERIVATIVES AND METHODS OF USE

The compositions and methods described herein relate generally to substituted tropolone derivatives, which, among other features, are useful as histone deacetylase (HDAC) inhibitors.

The furan route to tropolones: Probing the antiproliferative effects of β-thujaplicin analogs

A direct route to analogs of the naturally occurring tropolone β-thujaplicin has been developed in just four steps from furan. Using this method, a series of derivatives were synthesized and evaluated. Several of these compounds demonstrated very high levels of potency against bacterial and fungal pathogens with good selectivity over mammalian cells.

Regioselective synthesis of β- and γ-thujaplicins

β-Thujaplicin (hinokitiol) 1 and γ-thujaplicin 2, as the first naturally occurring monocyclic tropolone, were regioselectively synthesized from (R)-(+)-limonene, by using different dienyl silyl ether intermediates, 7 and 10, in 18% overall yield via 11 steps and 22% overall yield via 10 steps, respectively. (C) 2000 Elsevier Science Ltd.

Stereo- and regiocontrolled hydroxylation of oxyallyl [4+3] cycloadducts. A concise synthesis of hinokitiol

Stereo- and regioselective hydroxylation of 8-oxabicyclo[3.2.1]oct-6-en-3-ones was achieved by the action of (diacetoxyiodo)benzene in methanolic potassium hydroxide (the Moriarty oxidation). Subsequent double elimination afforded a convenient preparation of substituted tropolones, as exemplified in a three-step synthesis of hinokitiol (1).

The Palladium-Mediated Cross Coupling of Bromotropolones with Organostannanes or Arylboronic Acids: Applications to the Synthesis of Natural Products and Natural Product Analogues

The bromotropolones (4), (5) and (10) undergo palladium-mediated cross coupling with a wide range of organostannanes to produce alkenyl-, alkyl- and aryl-substituted tropolones.The methodology has been applied to the synthesis of the monoterpenes β-dolabrin (11), β-thujaplicin (12), 4-isopropyl-7-methoxytropolone (13) and β-thujaplicinol (14).Cross coupling of bromotropolones (4), (5) and (10) with various aryltrimethylstannanes or arylboronic acids has permitted the preparation of the bicyclic colchicine analogues (30)-(43) which have been tested for tubulin-binding activity.The X-ray crystal structure of the most active of these systems, compound (38), is reported.