35354-74-6

Basic information

• Product Name: Honokiol
• Synonyms: Honokiol,5,3′-Diallyl-2,4′-dihydroxybiphenyl;3',5-Diallyl-2,4'-dihydroxybiphenol;NSC 293100;Honokiol, froM Houpoea officinalis;Honokiol(NATURAL);3',5-di-2-propen-1-yl-[1,1'-biphenyl]-2,4'-diol;2-(4-hydroxy-3-prop-2-enyl-phenyl)- 4-prop-2-enyl-phenol;3',5-Diallyl-2,4'-dihydroxybiphenyl
• CAS NO: 35354-74-6
• Molecular Formula: C₁₈H₁₈O₂
• Molecular Weight: 266.33
• EINECS: 1592732-453-0
• Product Categories: Nutritional Ingredients;Plant extract;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;natural product;Inhibitors;Aromatic Phenols;The group of Magnolia;Antitumour
• Mol File: 35354-74-6.mol
• Article Data: 19

Chemical Properties

• Melting Point: 86℃
• Boiling Point: 400.1 °C at 760 mmHg
• Flash Point: 184 °C
• Appearance: /powder
• Density: 1.107 g/cm³
• Vapor Pressure: 5.65E-07mmHg at 25°C
• Refractive Index: 1.601
• Storage Temp.: 2-8°C
• Solubility: DMSO: 36 mg/mL
• PKA: 9.89±0.48(Predicted)
• Merck: 14,4742
• CAS DataBase Reference: Honokiol(CAS DataBase Reference)
• NIST Chemistry Reference: Honokiol(35354-74-6)
• EPA Substance Registry System: Honokiol(35354-74-6)

Safety Data

• Hazard Codes: Xi,N
• Statements: 41-51/53
• Safety Statements: 26-39-61
• RIDADR: UN 3077 9/PG 3
• WGK Germany: 3
• HazardClass: 9
• Hazardous Substances Data: 35354-74-6(Hazardous Substances Data)

Usage

Basic Information

Honokiol is the isomer of magnolol, being the dimer polymerized by the side chain of phenylpropane and another phenylpropyl benzene nucleus, called the neolignan. It was mainly found in the Lauraceae plants, being the active ingredients of antibacterial, anti-inflammatory of the traditional Chinese medicine Magnolia. Honokiol and magnolol appear as colorless needle crystal, being insoluble in water, soluble in chloroform, benzene, ethanol and caustic alkali. The physical and chemical constants were honokiol, mp: 102 ° C, UV λmaxEtOHnm (ε): 294 (8200); and honokiol, mp: 87.5 ° C, UV λmaxEtOHnm (ε): 294 nm (8200). Figure 1 shows the chemical formula of magnolol and honokiol. Magnolia is a commonly used Chinese medicine. First contained in the "Shen Nong's Herbal Classic", as the goods. Magnolia officinalis extract is a product derived from dried root bark, bark or shoots of Magnolia officinalis, etc. The product extracts usually standardize the contents of magnolol and honokiol.

Distribution

There were about 90 species of Magnoliaceae Magnolia plants around the world. There are about 30 species, of which there are about 20 kinds of medicinal value. Magnolia was born at fertile-soil, soil-deep sunny hillside, forest edge of an altitude of 300~1700 m. Magnolia is mainly distributed in western Hubei, southern Sichuan, southern Shaanxi and southern Gansu. Magnolia is mainly distributed in Jiangxi, Anhui, Zhejiang, Fujian, Hunan, Guangxi and northern Guangdong. Magnolia officinalis has a large area of artificial cultivation.

Main Ingredients

Magnolia bark contains magnolol, and honokiol, isomagnolol and other ingredients. It has been isolated of the trihydroxy honokiol, degausated trihydroxy glibenol, trihydroxy thick aldehydes, poly honokiol a, c. from the ethyl acetate extract of magnolia. Bark contains about 1% volatile oil, which mainly contains β-oleyl alcohol; still contain α-pinene, β-pinene and limonene. The bark also contains lignin. Its leaves also contain magnolol and honokiol. [Harvest and Processing] On April to June, pick off the dried bark growing for more than 15 years, and put into the boiling water for micro-cook, and put into the soil pits, covered with grass to "sweat". When the water comes from the internal seepage and the inner surface becomes purple brown or tan, further steamed soft, remove out, roll into tube-like, and dry it Root bark and branch, after being peel down, can be directly dried. Figure 2 is Magnolia.

Extraction method

1. Magnolia extract (flow extract) production process Take magnolia and crush it, infiltrate with ethanol for 12 hours, and place it into the percolation tube; apply 12 times the amount of ethanol for percolation; collect the percolation fluid; decompress and completely recycle the ethanol to obtain the flow extract with a yield of about 9% and the content of solid content being 85.0%. The product contains more than 11.0% of magnolol and over 5.0% honokiol. 2. Magnolol, and Honokiol extraction and separation Take the thick and dry powder of magnolia officinalis, add 1/5 amount (W / W) of lime powder, mix well; apply 15-20 times the amount of distilled water for percolation; the percolation fluid plus hydrochloric acid was adjusted to the pH value of 2 to 3, Stand still. The precipitate was collected and washed with distilled water until the pH of the precipitate was 6 to 7. After drying, alumina (1: 10) was added and homogenized, and the extractant was extracted with cyclohexane. The cyclohexane was concentrated and allowed to cool to precipitate out the white crystals; filter to give crystals and mother liquor. Crystal is recrystallized from cyclohexane, i.e., honokiol. The mother liquor is concentrated to crystallize, further re-crystallized by cyclohexane to give colorless flaky crystals, which are magnolol crystals. The yield of honokiol was 85%, and the yield of honokiol was 74%.

Pharmacological effects

1. The role of anti-pathogenic microorganisms Magnolia has inhibitory effect against Staphylococcus aureus, Streptococcus cholerae, Escherichia coli, Proteus, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Proteus Bacilli subtilis, diphtheria bacillus and other Gram-negative bacteria, of which it has the strongest inhibitory effect on Staphylococcus aureus. At the concentration of 15%, it has inhibitory effect against the skin fungi of experimental animals including small spore ringworm, genital trichophyton and Trichophyton rubrum. Magnolia decoctum has some effect on the improvement of parenchymal pathological damage in mice with experimental viral hepatitis. Magnolol had significant antibacterial activity against Gram-positive bacteria and acid-resistant bacteria. Magnolol had significant anti-caries effect and had a minimum inhibitory concentration of 6.3 μg / ml, and its antibacterial activity was stronger than that of typical antimicrobial alkaloids Berberine (MIC: 50 μg / ml). The saturated aqueous solution of the volatile oil of magnesium and Magnolia officinalis has certain antibacterial effect against Staphylococcus aureus, sarcina and Bacillus subtilis. 2. The role of the cardiovascular system Magnolol and honokiol inhibit the formation of thromboxane B2 in various cases, and the increase in intracellular Ca2 + caused by arachidonic acid or collagen is also inhibited by both of them. Honokiol can inhibit CaM to stimulate the activity of the cyclic nucleotide phosphodiesterase. Honokiol, in the presence of Ca2 +, can bind to CaM, thereby antagonizing its activation of phosphodiesterase. In addition, honokiol has a stimulating effect on the basal activity of CaM-dependent phosphodiesterase. 3. Antitumor effect Magnolol and its hydroxymethyl derivatives have a significant inhibitory effect against the second stage of mice skin tumors. The three extraction components of Magnolia officinalis, lignans, magnolol, and honokiol and monoterpene magnolol are the antagonist of the Epstein -Barr virus early antigen activation effect induced by the 12-O-tetradecanoyl phorbol-13-acetate (TPA). The methanol extract of Magnolia officinalis and magnolol has significant inhibitory effect on the mouse skin tumors induced by the two-stage in vivo carcinogenicity. The toxicity of Magnolia officinalis is relatively small. Magnolia decoction: LD50 of mice subjecting to intraperitoneal injection was 6.12 ± 0.038g / kg; the LD50 for lambda alkaloids subjecting to intraperitoneal injection was 45.55mg / kg. The MLD for cat subjecting to intravenous infusion was 4.25 ± 1.25g / kg. Under the general muscle relaxation dose, the ECG of the experimental animal is not affected. Large doses can cause respiratory depression and death. Pharmacokinetics 14C isotope tracer studies have shown that magnolol has rapid oral administration for rat; after 15 minutes, the plasma concentration reaches the peak. After oral administration of 1 hour, liver, kidney as well as stomach contains significant radioactive. The same results were obtained in 8 hours after 1 hour, and significant radioactivity was observed in the intestine. Magnolol, after subjecting intravenous infusion, is distributed in the brain, spinal cord, liver, stomach, intestine, kidney, lung, heart, muscle and other tissues. Intravenous administration can cause significant blacking in lungs after 1 hour. This is due to that the micro-particles of the magnolol suspension are caught in the lungs. Magnolol is mainly distributed in the liver with remarkable blacking also being found in the intestine. In other tissues, the radioactivity is basically uniform distributed. In the brain, it is also seen of a similar general distribution as muscle. 8 hours later, liver, lung and kidney still contain a number of radioactivities. Remarkable blacking could be seen in the intestine, and so for stomach. Based on the analysis of mass spectrometry, the main metabolites of Magnolol, which excreted in the fecal matter for the rats is M1, M2, M3, M4, M5, M6 and their glucuronic acid compounds and sulfates.

Clinical efficacy

Magnolia can be used to treat acute enteritis, bacterial or amoebic dysentery and chronic gastritis.

Application overview

Magnolia is a kind of traditional Chinese medicine, and has been included in many kinds of prescriptions. In recent years, domestic and foreign scholars, through the in-depth study of the active ingredients, pharmacodynamics and clinical pharmacy of Magnolia officinalis, have developed the Magnolia caries toothpaste, antibacterial “chewing gum” made of Magnolia extract that have been already marketed.

Description

Magnolol is derived from the root bark and branch bark of magnolia or Magnolia officinalis. Magnolia officinalis was first written in the《ben jing》, it prefers cool and humid climate and well-drained acid soil. Cortex magnoliae officinalis (hou po) is mainly produced in Sichuan (Wan quan, Shizhu, Guanxian), Hubei (Shien,Yichang, Lichuan), Zhejiang (Longquan, Anhui), and other places. It is also distributed in Fujian, Jiangxi, Hunan, Guangxi, Yunnan, Guizhou, Shanxi, Gansu, and other places. Cortex magnoliae officinalis from Sichuan and Hubei is called “chuan pu,” with better quality, while in Zhejiang, it is called “warm park,” with a larger output.

Physical properties

Appearance: white fine powder. Solubility: practically insoluble in water; very soluble in benzene, ethyl ether, chloroform, and acetone. Melting point: magnolol is 102 °C. Honokiol is 87.5 °C.

History

In 1930, magnolol was first isolated from the bark of Cortex magnoliae officinalis in China by Japanese Sugii, and it was also isolated from Cortex magnoliae officinalis in Japan. In 1973, magnolol and its isomers honokiol were isolated from Cortex magnoliae officinalis in China and Japan by Japanese Fujita. The drug research and development of magnolol and honokiol remain in pharmacological activity and preclinical research. Kyung Hee University from Korea declared a preclinical study in 2003, in which allergy, anxiety, angina, and heart failure are indications for honokiol.

Uses

Different sources of media describe the Uses of 35354-74-6 differently. You can refer to the following data:
1. Honokiol has been used:to study its effects on plasmid hSirt3102-399 deacetylation activityas an antioxidant to study its cytoprotective role in human ovarian cancer cells (SKOV-3) and Chinese hamster ovary cells (CHOK1)to explore its effects on oxidative stress and mitochondrial dysfunction via a sirt3-dependent mannerfor intracerebroventricular (ICV) cannulation
2. Honokiol is a small-molecule polyphenol isolated from the genus Magnolia. Recent studies show that Honokiol displays antiangiogenic, antiinflammatory, and antitumor properties in preclinical models, w ithout appreciable toxicity. Honokiol has been shown to inhibit the bone metastatic growth of human prostate cancer cells.

Indications

These compounds are recorded in the British Pharmacopoeia (2017) and European Pharmacopoeia (8.7th ed.). They are mainly used as antibacterial and antifungal agents.

General Description

Honokiol exhibits analgesic, antithrombotic, antispasmodic, antidepressant, antimicrobial and neuroprotective effects. It regulates gamma-aminobutyric acid (GABA) A receptors. Honokiol is associated with an increased risk of bleeding. It prevents platelet aggregation, protects myocardium from ischemic damage and inhibits ventricular arrhythmia.

Biochem/physiol Actions

Honokiol is a natural biphenyl neolignan from magnolia extract. It is antiangiogenic, antitumor, and anxiolytic.

Pharmacology

Magnolol and honokiol have the pharmacological effects of prolonging central muscle relaxation, inhibition of the central nervous, anti-inflammatory, antibacterial, antimicrobial, antiulcer, antioxidant, antitumor, hormone regulation, and antidiabetes .

InChI:InChI=1/C18H18O2/c1-3-5-13-7-9-18(20)16(11-13)14-8-10-17(19)15(12-14)6-4-2/h3-4,7-12,19-20H,1-2,5-6H2

Synthetic route

Dimethylhonokiol (68592-18-7) → Honokiol (35354-74-6)

Conditions	Yield
With aluminum (III) chloride at -5 - 0℃; for 0.333333h;	97%
With boron tribromide-dimethyl sulfide complex In 1,2-dichloro-ethane at 65℃; for 15h; Reagent/catalyst; Temperature; Inert atmosphere;	95%
Stage #1: Dimethylhonokiol With triethylsilane; tris(pentafluorophenyl)borate In dichloromethane at 20℃; for 0.333333h; Inert atmosphere; Schlenk technique; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #3: With water In tetrahydrofuran	57.8%

3,5′-diallyl-2′-methoxy-[1,1′-biphenyl]-4-ol (68592-19-8) → Honokiol (35354-74-6)

Conditions	Yield
With boron trichloride - methyl sulfide complex In dichloromethane; 1,2-dichloro-ethane for 18h; Reflux;	91%
With boron tribromide In dichloromethane at 20℃; for 0.416667h; Inert atmosphere;	90%
With boron tribromide at -15 - 20℃;
With boron tribromide In dichloromethane at 20℃; for 0.416667h; Inert atmosphere;	430 mg

5-allyl-4'-(allyloxy)-[1,1'-biphenyl]-2-ol (108886-93-7) → Honokiol (35354-74-6)

Conditions	Yield
With N,N-diethylaniline at 200℃; for 24h; Claisen Rearrangement; Sealed tube; Schlenk technique; Inert atmosphere;	90%
With boron trichloride In chlorobenzene at -15℃; for 1h;	80%

5,3'-diallyl-2,4'-bis-methoxymethoxy-biphenyl (711012-14-5) → Honokiol (35354-74-6)

Conditions	Yield
With hydrogenchloride In methanol at 20℃; for 44h;	89%

3,5'-diallyl-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-ol → Honokiol (35354-74-6)

Conditions	Yield
With methanol; chloro-trimethyl-silane at 0 - 20℃; for 6h;	85%

2,4'-bis-O-allylbiphenyl (911812-86-7) → 3,3'-diallyl biphenyl-2,4'-diol + Honokiol (35354-74-6)

Conditions	Yield
for 1.33333h; Claisen Rearrangement; Microwave irradiation; Heating; Sealed tube;	A 40% B 60%
at 180℃; for 1.33333h; Claisen Rearrangement; Microwave irradiation;	A 40% B 60%
at 190℃; for 12h; Claisen Rearrangement; Sealed tube;	A 55% B 40%
at 190℃; for 12h; Claisen Rearrangement; Sealed tube;	A 55% B 40%

5-allyl-4'-(allyloxy)-2-methoxybiphenyl (1133087-04-3) → Honokiol (35354-74-6) + 5-allyl-[1,1'-biphenyl]-2,4'-diol (1253950-18-3)

Conditions	Yield
With boron trichloride - methyl sulfide complex In dichloromethane; 1,2-dichloro-ethane for 18h; Claisen rearrangement; Reflux;	A 47% B 49%

eudeshonokiol A (126654-55-5) → Honokiol (35354-74-6) + cryptomeridiol (60132-35-6, 92857-25-5, 108006-39-9, 122674-21-9, 143004-65-3, 4666-84-6)

Conditions	Yield
With trifluoroacetic acid In benzene

eudeshonokiol A (126654-55-5) → Honokiol (35354-74-6) + eudesm-4-en-11-ol (13902-07-3, 15051-81-7, 72173-98-9, 98683-12-6, 117066-77-0, 1209-71-8)

Conditions	Yield
With trifluoroacetic acid In benzene for 10h; Ambient temperature;	A 7 mg B 3 mg

5-bromosalicyclic acid (89-55-4) → Honokiol (35354-74-6)

Conditions

Yield

Multi-step reaction with 9 steps 1: 100 percent / aq. H2SO4 / Heating 2: 100 percent / i-Pr2NEt / dimethylformamide / 3 h / 20 °C 3: 86 percent / PdCl2(dppf); dppf; AcOK / dioxane / 80 °C 4: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 5: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 6: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 7: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 8: 52 percent / CuI / tetrahydrofuran / -26 °C 9: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

methyl 3-bromo-4-hydroxybenzoate (29415-97-2) → Honokiol (35354-74-6)

Conditions

Yield

Multi-step reaction with 9 steps 1: 98 percent / i-Pr2NEt / dimethylformamide / 3 h / 20 °C 2: 100 percent / DIBAL-H / CH2Cl2 / 2 h / -78 °C 3: 100 percent / imidazole / dimethylformamide / 20 °C 4: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 5: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 6: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 7: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 8: 52 percent / CuI / tetrahydrofuran / -26 °C 9: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

5-bromo-2-hydroxy-benzoic acid methyl ester (4068-76-2) → Honokiol (35354-74-6)

Conditions

Yield

Multi-step reaction with 8 steps 1: 100 percent / i-Pr2NEt / dimethylformamide / 3 h / 20 °C 2: 86 percent / PdCl2(dppf); dppf; AcOK / dioxane / 80 °C 3: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 4: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 5: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 6: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 7: 52 percent / CuI / tetrahydrofuran / -26 °C 8: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

methyl 4-hydroxylbenzoate (99-76-3) → Honokiol (35354-74-6)

Conditions

Yield

Multi-step reaction with 10 steps 1: 80 percent / HBF4; N-bromosuccinimide / acetonitrile / -20 - 20 °C 2: 98 percent / i-Pr2NEt / dimethylformamide / 3 h / 20 °C 3: 100 percent / DIBAL-H / CH2Cl2 / 2 h / -78 °C 4: 100 percent / imidazole / dimethylformamide / 20 °C 5: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 6: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 7: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 8: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 9: 52 percent / CuI / tetrahydrofuran / -26 °C 10: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

(3-bromo-4-methoxymethoxy-phenyl)-methanol (162269-91-2) → Honokiol (35354-74-6)

Conditions

Yield

Multi-step reaction with 7 steps 1: 100 percent / imidazole / dimethylformamide / 20 °C 2: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 3: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 4: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 5: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 6: 52 percent / CuI / tetrahydrofuran / -26 °C 7: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

5-bromo-2-methoxymethoxy-benzoic acid methyl ester (711012-12-3) → Honokiol (35354-74-6)

Conditions

Yield

Multi-step reaction with 7 steps 1: 86 percent / PdCl2(dppf); dppf; AcOK / dioxane / 80 °C 2: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 3: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 4: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 5: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 6: 52 percent / CuI / tetrahydrofuran / -26 °C 7: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

3-bromo-4-methoxymethoxybenzoic acid methyl ester (672922-57-5) → Honokiol (35354-74-6)

Conditions

Yield

Multi-step reaction with 8 steps 1: 100 percent / DIBAL-H / CH2Cl2 / 2 h / -78 °C 2: 100 percent / imidazole / dimethylformamide / 20 °C 3: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 4: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 5: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 6: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 7: 52 percent / CuI / tetrahydrofuran / -26 °C 8: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

(3-bromo-4-methoxymethoxy-benzyloxy)-tert-butyl-dimethyl-silane (711012-11-2) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 2: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 3: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 4: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 5: 52 percent / CuI / tetrahydrofuran / -26 °C 6: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

4-hydroxy-benzoic acid (99-96-7) + acid → Honokiol (35354-74-6)

Conditions

Yield

Multi-step reaction with 11 steps 1: 99 percent / aq. H2SO4 / Heating 2: 80 percent / HBF4; N-bromosuccinimide / acetonitrile / -20 - 20 °C 3: 98 percent / i-Pr2NEt / dimethylformamide / 3 h / 20 °C 4: 100 percent / DIBAL-H / CH2Cl2 / 2 h / -78 °C 5: 100 percent / imidazole / dimethylformamide / 20 °C 6: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 7: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 8: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 9: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 10: 52 percent / CuI / tetrahydrofuran / -26 °C 11: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

2-methoxymethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (711012-10-1) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: 87 percent / PdCl2(dppf); dppf; K3PO4 / dioxane / 108 °C 2: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 3: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 4: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 5: 52 percent / CuI / tetrahydrofuran / -26 °C 6: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

5,3'-bis-bromomethyl-2,4'-bis-methoxymethoxy-biphenyl (711012-16-7) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 52 percent / CuI / tetrahydrofuran / -26 °C 2: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

(3'-hydroxymethyl-6,4'-bis-methoxymethoxy-biphenyl-3-yl)-methanol (711012-13-4) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 2: 52 percent / CuI / tetrahydrofuran / -26 °C 3: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

5'-(tert-butyl-dimethyl-silanyloxymethyl)-4,2'-bis-methoxymethoxy-biphenyl-3-carboxylic acid methyl ester (711012-09-8) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: 99 percent / LiAlH4 / tetrahydrofuran / 0 °C 2: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 3: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 4: 52 percent / CuI / tetrahydrofuran / -26 °C 5: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

[5'-(tert-butyl-dimethyl-silanyloxymethyl)-4,2'-bis-methoxymethoxy-biphenyl-3-yl]-methanol (711012-15-6) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 98 percent / HF; pyridine / acetonitrile / 1 h / 20 °C 2: 80 percent / N-bromosuccinimide; triphenylphosphine / CH2Cl2 3: 52 percent / CuI / tetrahydrofuran / -26 °C 4: 89 percent / aq. HCl / methanol / 44 h / 20 °C View Scheme

4-(prop-2-enyl)phenol (501-92-8) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 29.2 percent / acetic acid / 0.25 h / Ambient temperature 2: 1.) methyl iodide, Mg / 1.) ether, reflux, 5 h; 2.) ether, -15 deg C, 30 min 3: 80 percent / BCl3 / chlorobenzene / 1 h / -15 °C View Scheme

1-allyl-4-oxocyclohexa-2,5-dienylethanoate (108886-90-4) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) methyl iodide, Mg / 1.) ether, reflux, 5 h; 2.) ether, -15 deg C, 30 min 2: 80 percent / BCl3 / chlorobenzene / 1 h / -15 °C View Scheme

methylhonokiol (68592-15-4) → Honokiol (35354-74-6)

Conditions	Yield
Stage #1: methylhonokiol With boron tribromide In dichloromethane at -78℃; Stage #2: With water
Grignard reaction;

5-allyl-4'-(allyloxy)-2-methoxybiphenyl (1133087-04-3) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: diethylaluminium chloride / hexane / 2 h / 20 °C / Inert atmosphere 2: boron tribromide / dichloromethane / 0.42 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: diethylaluminium chloride / hexane / 2 h / 20 °C / Inert atmosphere 2: boron tribromide / dichloromethane / 0.42 h / 20 °C / Inert atmosphere View Scheme

4-allyl-2-bromo-1-methoxybenzene (87688-94-6) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / water; acetone; tert-butyl alcohol / 24 h / 20 °C / Inert atmosphere 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / 1,2-dimethoxyethane; water / 18 h / 80 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / Inert atmosphere; Cooling with ice 3.2: 2.08 h / 20 °C / Inert atmosphere 3.3: 18 h / 140 °C / Inert atmosphere 4.1: sodium iodide; zinc / N,N-dimethyl-formamide / 18 h / 140 °C / Inert atmosphere 5.1: potassium carbonate / acetone / 20 °C / Inert atmosphere 6.1: diethylaluminium chloride / hexane / 2 h / 20 °C / Inert atmosphere 7.1: boron tribromide / dichloromethane / 0.42 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: osmium(VIII) oxide; water; 4-methylmorpholine N-oxide / acetone; tert-butyl alcohol / 24 h / 20 °C / Inert atmosphere 2.1: sodium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane; water / 18 h / 80 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / Inert atmosphere; Cooling 3.2: 2 h / 20 °C / Inert atmosphere; Cooling 3.3: 18 h / 140 °C / Inert atmosphere 4.1: potassium carbonate / acetone / 20 °C / Inert atmosphere 5.1: diethylaluminium chloride / hexane / 2 h / 20 °C / Inert atmosphere 6.1: boron tribromide / dichloromethane / 0.42 h / 20 °C / Inert atmosphere View Scheme

5'-allyl-2'-methoxy-biphenyl-4-ol (1133087-02-1) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 20 °C / Inert atmosphere 2: diethylaluminium chloride / hexane / 2 h / 20 °C / Inert atmosphere 3: boron tribromide / dichloromethane / 0.42 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 20 °C / Inert atmosphere 2: diethylaluminium chloride / hexane / 2 h / 20 °C / Inert atmosphere 3: boron tribromide / dichloromethane / 0.42 h / 20 °C / Inert atmosphere View Scheme

3-(3-bromo-4-methoxy-phenyl)-propane-1,2-diol (1355483-89-4) → Honokiol (35354-74-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / 1,2-dimethoxyethane; water / 18 h / 80 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0.5 h / Inert atmosphere; Cooling with ice 2.2: 2.08 h / 20 °C / Inert atmosphere 2.3: 18 h / 140 °C / Inert atmosphere 3.1: sodium iodide; zinc / N,N-dimethyl-formamide / 18 h / 140 °C / Inert atmosphere 4.1: potassium carbonate / acetone / 20 °C / Inert atmosphere 5.1: diethylaluminium chloride / hexane / 2 h / 20 °C / Inert atmosphere 6.1: boron tribromide / dichloromethane / 0.42 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: sodium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane; water / 18 h / 80 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0.5 h / Inert atmosphere; Cooling 2.2: 2 h / 20 °C / Inert atmosphere; Cooling 2.3: 18 h / 140 °C / Inert atmosphere 3.1: potassium carbonate / acetone / 20 °C / Inert atmosphere 4.1: diethylaluminium chloride / hexane / 2 h / 20 °C / Inert atmosphere 5.1: boron tribromide / dichloromethane / 0.42 h / 20 °C / Inert atmosphere View Scheme

Honokiol (35354-74-6) + benzoyl chloride (98-88-4) → 3',5-diallyl-2,4'-diphenylformyloxybiphenyl

Conditions	Yield
With dmap; triethylamine In dichloromethane at 20℃; for 1h; Cooling with ice;	98.4%

Honokiol (35354-74-6) + allyl bromide (106-95-6) → 3',5-diallyl-2,4'-bis(allyloxy)-1,1'-biphenyl

Conditions	Yield
With potassium carbonate In acetone at 56℃; for 12h;	97%

formaldehyd (50-00-0) + Honokiol (35354-74-6) + ethylamine (75-04-7) → C26H32N2O2

Conditions	Yield
In 1,4-dioxane; toluene at 120℃; for 24h;	95.5%

formaldehyd (50-00-0) + hexan-1-amine (111-26-2) + Honokiol (35354-74-6) → C34H48N2O2

Conditions	Yield
In 1,4-dioxane; toluene at 110℃; for 43h;	95.5%

Honokiol (35354-74-6) + acetic anhydride (108-24-7) → 2,4'-diacetoxy-5,3'-di(2-propenyl)biphenyl (35347-50-3)

Conditions	Yield
With pyridine	95%
With potassium carbonate at 20℃; for 0.5h;	56%
With pyridine at 25℃; for 18h;
With sodium hydrogencarbonate In ethyl acetate for 48h;

Honokiol (35354-74-6) → Tetrahydrohonokiol (35406-31-6)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol for 5h; Reflux;	94%
With sodium tetrahydroborate; nickel dichloride	70%
With hydrogen; palladium on activated charcoal
With palladium on activated charcoal; hydrogen
With Lindlar's catalyst; hydrogen In ethanol at 20℃; under 760.051 Torr; for 24h;

formaldehyd (50-00-0) + Honokiol (35354-74-6) + aniline (62-53-3) → C34H32N2O2

Conditions	Yield
In 1,4-dioxane; toluene at 100℃; for 58h;	93.6%

formaldehyd (50-00-0) + furan-2-ylmethanamine (617-89-0) + Honokiol (35354-74-6) → C32H32N2O4

Conditions	Yield
In 1,4-dioxane; toluene at 100℃; for 52h;	90.8%

4-Nitrophthalonitrile (31643-49-9) + Honokiol (35354-74-6) → C34H22N4O2

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 40℃; for 48h; Inert atmosphere;	90%

Honokiol (35354-74-6) + ethyl bromoacetate (105-36-2) → diethyl 2,2'-((3',5-diallyl-[1,1'-biphenyl]-2,4'-diyl)bis(oxy))diacetate (1333391-01-7)

Conditions	Yield
Stage #1: Honokiol With potassium carbonate In N,N-dimethyl-formamide at 20 - 25℃; Williamson synthesis; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide at 30℃; for 6h; Williamson synthesis;	89.3%

Honokiol (35354-74-6) → 4-allyl-2-(2-methyl-benzofuran-5-yl)phenol (1416567-14-0)

Conditions	Yield
With oxygen; sodium acetate; palladium dichloride In N,N-dimethyl acetamide; water at 60℃; under 6080.41 Torr; for 16h; Autoclave;	86%
With oxygen; sodium acetate; palladium dichloride In N,N-dimethyl acetamide; water at 60℃; under 6080.41 Torr; for 16h; Autoclave;	86%
With oxygen; sodium acetate; palladium dichloride In N,N-dimethyl acetamide; water at 60℃; under 6000.6 Torr; for 16h; Wacker Oxidation;	86%

formaldehyd (50-00-0) + Honokiol (35354-74-6) + dimethyl amine (124-40-3) → 3',5-diallyl-3,5'-bis((dimethylamino)methyl)-[1,1'-biphenyl]-2,4'-diol

Conditions	Yield
In methanol; water at 20℃; for 16h;	86%
Stage #1: formaldehyd; dimethyl amine With hydrogenchloride In methanol; water at 2 - 35℃; for 1h; Stage #2: Honokiol In methanol; water at 75℃; for 6h;	60%

Honokiol (35354-74-6) + methyl iodide (74-88-4) → Dimethylhonokiol (68592-18-7)

Conditions	Yield
With potassium carbonate In acetone for 24h; Reflux;	84%
With sodium hydride In water; dimethyl sulfoxide at 0℃;	38%

Honokiol (35354-74-6) → 3',5-diallyl-3,5'-dinitroso-1,1'-biphenyl-2,4'-diphenol

Conditions	Yield
With hydrogenchloride; sodium nitrite In water; acetonitrile at 20℃; for 1.5h; Cooling with ice;	79%
With hydrogenchloride; sodium nitrite In water; acetonitrile at 20℃; for 1.5h;	79.3%

Honokiol (35354-74-6) + 3-bromo-1-phenyl-1-propenyl bromide (4392-24-9) → 3',5-diallyl-2E,4'E-bis(cinnamyloxy)-1,1'-biphenyl

Conditions	Yield
With potassium carbonate In acetone at 60℃;	78%

Honokiol (35354-74-6) + dimethyl sulfoxide (67-68-5) → 4-allyl-2-(2-((methylthio)methyl)-2,3-dihydrobenzofuran-5-yl)phenol

Conditions	Yield
With ammonium iodide at 130℃; for 18h; Schlenk technique;	76%

formaldehyd (50-00-0) + Honokiol (35354-74-6) + dimethyl amine (124-40-3) → C21H25NO2

Conditions	Yield
Stage #1: formaldehyd; dimethyl amine In water at 55℃; for 0.666667h; Mannich Aminomethylation; Stage #2: Honokiol In water	76%

Honokiol (35354-74-6) + methyl 2-(2-chlorophenyl)-2-diazoacetate (264882-00-0) → methyl 2-(2-chlorophenyl)-2-((5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl)oxy)acetate

Conditions	Yield
With sewage sludge-derived carbon material treated with perchloric acid In 1,2-dichloro-ethane at 70℃; for 24h;	72%

Honokiol (35354-74-6) + dimethyl sulfate (77-78-1) → Dimethylhonokiol (68592-18-7)

Conditions	Yield
With sodium In ethanol for 5h; Inert atmosphere; Reflux;	70%

Honokiol (35354-74-6) → 3,3'-(4,6'-dihydroxy-[1,1'-biphenyl]-3,3'-diyl)bis(propane-1,2-diol)

Conditions	Yield
Stage #1: Honokiol With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 2h; Stage #2: With sodium hydroxide In tetrahydrofuran for 1h; Reflux;	66%
Multi-step reaction with 2 steps 1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 2: sodium hydroxide; water / tetrahydrofuran / 1 h / Reflux View Scheme

Honokiol (35354-74-6) → C18H17IO2

Conditions	Yield
With iodine In ethanol; water at 50℃; for 12h;	65.87%

formaldehyd (50-00-0) + Honokiol (35354-74-6) → 3',5-diallyl-3,5'-bis(hydroxymethyl)biphenyl-2,4'-diol (1333391-05-1)

Conditions	Yield
With sodium hydroxide In water at 20℃; for 24h;	63.15%

Honokiol (35354-74-6) → 3',5-aiallyl-3,5'-dinitro-[1,1'-biphenyl]-2,4'-diol

Conditions	Yield
Stage #1: Honokiol With acetic acid In dichloromethane for 0.0833333h; Cooling with ice; Stage #2: With nitric acid In dichloromethane at 0℃; for 6h;	61.3%
With nitric acid; acetic acid In dichloromethane at 10 - 20℃; for 1h;	52%

Honokiol (35354-74-6) + cyanomethyl bromide (590-17-0) → C22H20N2O2

Conditions	Yield
With caesium carbonate; potassium iodide In acetone at 20℃; for 24h;	61%

Upstream product

• 1133087-04-3 5-allyl-4'-(allyloxy)-2-methoxybiphenyl 
• 68592-15-4 methylhonokiol 
• 35347-50-3 2,4'-diacetoxy-5,3'-di(2-propenyl)biphenyl 
• 611-62-1 2,4'-dihydroxybiphenyl 
• 95-56-7 2-hydroxybromobenzene 
• 89-55-4 5-bromosalicyclic acid 
• 126654-55-5 eudeshonokiol A 
• 5720-06-9 2-Methoxyphenylboronic acid 
• 65461-42-9 4-Allyl-2-amino-phenol 
• 25244-30-8 4-(allyloxy)bromobenzene 
• 70482-71-2 1-allyl-4-(methoxymethoxy)benzene 
• 25458-45-1 p-methoxymethoxybromobenzene 
• 106-41-2 4-bromo-phenol 
• 2409-55-4 2-tert-Butyl-4-methylphenol 

Downstream Products

• 68592-19-8 3,5′-diallyl-2′-methoxy-[1,1′-biphenyl]-4-ol 
• 68592-15-4 methylhonokiol 
• 68592-18-7 Dimethylhonokiol 

Relevant articles and documents

Efficient synthesis of neurotrophic honokiol using Suzuki-Miyaura reactions

Efficient synthesis of honokiol (1) was accomplished using two kinds of Suzuki-Miyaura reactions. The first Suzuki-Miyaura reaction was employed to couple 2-bromophenol (6) with 4-hydroxyphenylboronic acid (5), giving rise to biphenol 4, and the second co

In vitro metabolism and disposition of honokiol in rat and human livers

The biotransformation of honokiol, a major constituent of the bark of Magnolia officinalis, was investigated in rat and human livers. When isolated, rat livers were perfused with 10μM honokiol and two metabolites, namely hydroxylated honokiol conjugated with glucuronic and sulfuric acid (M1) and honokiol monoglucuronide (M2), were quantified in bile and perfusate by high-performance liquid chromatography. The hepatic extraction ratio and clearance of honokiol was very high in rat liver (E: 0.99 ± 0.01 and 35.8 ± 0.04mL/min, respectively) leading to very low bioavailability (F = 0.007 ± 0.001). M2 formation was also highly efficient in human liver microsomes [Vmax/Km = 78.1 ± 6.73 μL/(min mg)], which appeared to be catalyzed mainly by UDP-glucuronosyltransferases 1A1, A3, 1A8, and 1A10, indicating hepatic and extrahepatic glucuronidation. Monosulfation of honokiol to the minor metabolite honokiol monosulfate [Vmax/Km = 27.9 ± 4.33 μL/(min mg)] by human liver cytosol was less pronounced and is mediated by sulfotransferases 1A1* 1, 1A1* 2, 1A2, 1A3, 1B1, and 1E1. P450-mediated oxidation of honokiol by liver microsomes, however, was below detection limit. In summary, this study established that glucuronidation and sulfation are the main metabolic pathways for honokiol in rat and human liver, suggesting their major contribution to clearance in vivo.

A concise synthesis of honokiol

A simple synthesis of the natural product honokiol 1 has been developed which proceeds in four steps and provides a 32% overall yield. Suzuki coupling of 4-allyl-2-bromoanisole 3 with 4-hydroxyphenyl boronic acid, followed by allylation, gave 5-allyl-4′-a

Gram Scale Synthesis of Honokiol

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Concise and practical approach for the synthesis of honokiol, a neurotrophic agent

An improved method has been developed for the synthesis of honokiol using a readily available p-bromophenol as a precursor. The key step involved in this method is ortho-lithiation facilitated by methoxymethyl ether (MOM). Other important steps are ortho-allyl phenyl ether Claisen rearrangement and a Suzuki coupling for the construction of biaryls. This method does not require pre-functionalization of aromatic ring with bromide for the generation of arylboronic acid.