486-84-0

Basic information

• Product Name: HARMANE
• Synonyms: METHYLCARBOLINE;METHYL-4-CARBOLINE;TIMTEC-BB SBB003735;1-Methyl-9H-beta-carboline;1-Methyl-9H-pyrid(3,4-b)indole;1-Methyl-9H-β-carboline;1-Methyl-beta-carboline;1-Methylnorharman
• CAS NO: 486-84-0
• Molecular Formula: C₁₂H₁₀N₂
• Molecular Weight: 182.22
• EINECS: 207-642-2
• Product Categories: Heterocyclic Compounds;Indole Derivatives;Mutagenesis Research Chemicals
• Mol File: 486-84-0.mol
• Article Data: 61

Chemical Properties

• Melting Point: 235-238 °C(lit.)
• Boiling Point: 305.62°C (rough estimate)
• Flash Point: 176.2°C
• Appearance: /
• Density: 1.1485 (rough estimate)
• Vapor Pressure: 7.61E-06mmHg at 25°C
• Refractive Index: 1.6266 (estimate)
• Storage Temp.: Store at RT
• Solubility: methanol: soluble50mg/ml
• PKA: 7.37, 14.6(at 25℃)
• Water Solubility: 1523g/L(20 oC)
• Merck: 13,4630
• BRN: 143898
• CAS DataBase Reference: HARMANE(CAS DataBase Reference)
• NIST Chemistry Reference: HARMANE(486-84-0)
• EPA Substance Registry System: HARMANE(486-84-0)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 20/21-36/37/38
• Safety Statements: 22-24/25-36-26
• RIDADR: 1544
• WGK Germany: 3
• RTECS: UV0280000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 486-84-0(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

Harmane was used in trace level determination of harmane by planar chromatography coupled with (tandem) mass spectrometry. It was used to study interactions of norharman and harman with DNA.It may be used as matrix for analysis of cyclodextrins and for sulfated oligosaccharides in combination with DHB as co-matrix.

Definition

ChEBI: An indole alkaloid fundamental parent with a structure of 9H-beta-carboline carrying a methyl substituent at C-1. It has been isolated from the bark of Sickingia rubra, Symplocus racemosa, P ssiflora incarnata, Peganum harmala, Banisteriopsis caapi and Tribulus terrestris, as well as from tobacco smoke. It is a specific, reversible inhibitor of monoamine oxidase A.

Synthesis Reference(s)

The Journal of Organic Chemistry, 37, p. 1429, 1972 DOI: 10.1021/jo00974a030Tetrahedron, 49, p. 3325, 1993 DOI: 10.1016/S0040-4020(01)90161-9

General Description

Harmane is a potent tremor-producing β-carboline alkaloid and neurotoxin.It is major representative of heterocyclic aromatic amines, a group of mutagenic and carcinogenic substances which are formed in meat from the precursors creatine, creatinine, amino acids and sugars during the heating at high temperatures.Blood harmane concentration is elevated in essential tremor, late-life neurological disease.

Biological Activity

Proposed as the endogenous ligand for imidazoline binding sites. Binds to I 1 -sites in rat kidney with an IC 50 of 31 nM, and I 2 -sites with a K i of 49 nM. In vivo, produces a dose-dependent hypotension that is reversed by efaroxan (2-(2-Ethyl-2,3-dihydro-2-benzofuranyl)-4,5-dihydro-1H-imidazole hydrochloride ). Also a potent inhibitor of monoamine oxidases A and B (I 50 values are 0.5 and 5 μ M respectively).

Biochem/physiol Actions

I1 imidazoline binding site agonist.

InChI:InChI=1/C12H10N2/c1-8-12-10(6-7-13-8)9-4-2-3-5-11(9)14-12/h2-7,14H,1H3

Synthetic route

tryptamine (61-54-1) + acetaldehyde (75-07-0) → harmane (486-84-0)

Conditions	Yield
With acid	88.7%
Stage #1: tryptamine; acetaldehyde With piperidine; methanesulfonic acid at 100℃; for 4h; Sealed tube; Stage #2: With triethylamine In water Stage #3: With palladium on activated charcoal at 180℃; for 5h; Reagent/catalyst; Temperature; Inert atmosphere;	80.2%
Yield given;

eleagnine (2506-10-7) → harmane (486-84-0)

Conditions	Yield
With C21H21ClIrNO2 In tetrahydrofuran; 2,2,2-trifluoroethanol for 20h; Inert atmosphere;	93%
With [bis(acetoxy)iodo]benzene In N,N-dimethyl-formamide at 20℃; for 1h;	84%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; copper(ll) bromide In dimethyl sulfoxide at 25℃; for 24h; Green chemistry;	81%

1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid (5470-37-1, 40678-46-4, 42438-72-2, 96149-76-7, 98718-62-8, 114497-71-1, 143396-05-8) → harmane (486-84-0)

Conditions	Yield
With tetrasodium cobalt(II) 4,4',4'',4'''-tetrasulphophthalocyanine In water; ethyl acetate at 20℃; for 24h; Irradiation; Green chemistry;	87%
With ammonium persulfate; silver nitrate In water; acetonitrile at 80℃;	56%
Multi-step reaction with 2 steps 1: acetic acid; water / 0.33 h / 100 °C 2: sodium hydroxide; sodium hydrogensulfite View Scheme
With manganese(IV) oxide; sulfuric acid

(3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (191279-37-5) → harmane (486-84-0)

Conditions	Yield
With copper dichloride In N,N-dimethyl-formamide at 130℃; for 1h;	84%
With N-chloro-succinimide; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5h;	82%
With iron(III) chloride In N,N-dimethyl-formamide at 130℃; for 1h; Catalytic behavior; Green chemistry;	82%

1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole trifluoroacetate → harmane (486-84-0)

Conditions	Yield
With 2 mol-% Pd/C; lithium carbonate In ethanol at 150℃; for 0.166667h; Sealed tube; Microwave irradiation;	93%
With lithium carbonate; silver carbonate In N,N-dimethyl-formamide for 1h; Reflux;	34%

1-methyl-4,9-dihydro-3H-β-carboline (525-41-7) → harmane (486-84-0)

Conditions	Yield
With potassium permanganate In acetone at 20℃;	92%
With C21H21ClIrNO2 In tetrahydrofuran; 2,2,2-trifluoroethanol for 20h; Inert atmosphere;	81%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 125℃; for 10h;	76%

C14H15NO2 → harmane (486-84-0)

Conditions	Yield
With ammonium acetate In acetic acid; N,N-dimethyl-formamide at 120℃; for 7h;	90 mg

C13H16N2O2 → harmane (486-84-0)

Conditions	Yield
Stage #1: C13H16N2O2 With manganese(IV) oxide In water at 100℃; for 0.0833333h; Stage #2: With sulfuric acid In water at 100℃; for 1h;

N-Acetyltryptamine (1016-47-3) → harmane (486-84-0)

Conditions	Yield
Stage #1: N-Acetyltryptamine With trifluoromethylsulfonic anhydride; Triphenylphosphine oxide In chlorobenzene at 20 - 130℃; Stage #2: With manganese(IV) oxide In chlorobenzene at 130℃; for 4h;	82%
Stage #1: N-Acetyltryptamine With trifluoromethylsulfonic anhydride; Triphenylphosphine oxide In chlorobenzene Stage #2: With manganese(IV) oxide In chlorobenzene	80%
With trichlorophosphate In toluene; acetonitrile for 3h; Reflux;

1-methyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (5159-20-6) → harmane (486-84-0)

Conditions	Yield
With oxygen; sodium hydroxide In water; dimethyl sulfoxide at 125℃; for 5h;	82%
Stage #1: 1-methyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole In tetrahydrofuran at -78℃; for 2h; Stage #2: With oxygen In tetrahydrofuran at 20℃;	74%

1-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-b]indole (31965-09-0) → harmane (486-84-0)

Conditions	Yield
With palladium on activated carbon In diphenylether at 210℃; for 0.66h; Inert atmosphere;	91%
With palladium on activated charcoal; diphenylether; biphenyl

(+/-)-Calligonine hydrochloride (6678-82-6) → harmane (486-84-0)

Conditions	Yield
With 5 mol% Pd/C; lithium carbonate In ethanol at 150℃; for 0.1h; Sealed tube; Microwave irradiation;	92%

6-bromo-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride → harmane (486-84-0)

Conditions	Yield
With 5 mol% Pd/C; lithium carbonate In ethanol at 150℃; for 0.75h; Sealed tube; Microwave irradiation;	75%

3-azido-2-methyl-4-phenylpyridine → harmane (486-84-0)

Conditions	Yield
In 5,5-dimethyl-1,3-cyclohexadiene for 10h; Reflux;	45%

tert.-butylhydroperoxide (75-91-2) + betacarboline (244-63-3) → harmane (486-84-0)

Conditions	Yield
With iron(II) sulfate In sulfuric acid; water; acetic acid at 0℃; for 2h;	75%

6-chloro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride → harmane (486-84-0)

Conditions	Yield
With 5 mol% Pd/C; lithium carbonate In ethanol at 150℃; for 0.1h; Sealed tube; Microwave irradiation;	60%

N,N-dimethyl acetamide (127-19-5) + 1-(phenylsulfonyl)-3-vinyl-1H-indole (82980-12-9) → harmane (486-84-0)

Conditions	Yield
Stage #1: 3-ethenyl-1-phenylsulfonyl-1H-indole With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: N,N-dimethyl acetamide In tetrahydrofuran at -78 - -10℃; Stage #3: With hydroxylamine hydrochloride; sodium acetate In 1,2-dichloro-benzene for 8h; Heating;	46%

N,N-dimethyl acetamide (127-19-5) + (E)-1-(Phenylsulfonyl)-3-(β-methoxyvinyl)indole (110128-40-0) → harmane (486-84-0)

Conditions	Yield
Stage #1: (E)-1-(Phenylsulfonyl)-3-(β-methoxyvinyl)indole With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: N,N-dimethyl acetamide In tetrahydrofuran at -78 - -10℃; Stage #3: With hydroxylamine hydrochloride; sodium acetate In 1,2-dichloro-benzene for 8h; Heating;	53%

N,N-dimethyl acetamide (127-19-5) + (E)-3-(2-nitrovinyl)-1-(phenylsulfonyl)-1H-indole (211738-25-9) → harmane (486-84-0)

Conditions	Yield
Stage #1: (E)-3-(2-nitrovinyl)-1-(phenylsulfonyl)-1H-indole With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: N,N-dimethyl acetamide In tetrahydrofuran at -78 - -10℃; Stage #3: With hydroxylamine hydrochloride; sodium acetate In 1,2-dichloro-benzene for 8h; Heating;	45%

L-Tryptophan (73-22-3) → harmane (486-84-0)

Conditions	Yield
With sulfuric acid; acetaldehyde Oxydieren der Reaktionsloesung mit Kaliumdichromat;
With acetic anhydride; zinc(II) chloride Oxydieren des entstandenen Oels mit Chromschwefelsaeure;
Multi-step reaction with 2 steps 1: acetic acid / 3 h / Reflux 2: acetic acid; potassium dichromate / water / 0.33 h / 100 °C View Scheme

2,2-dimethyl-N-(2-(3-fluoro-2-methyl-4-pyridyl)phenyl)propanamide → harmane (486-84-0)

Conditions	Yield
With pyridine hydrochloride at 210℃; for 0.25h;	84%

tryptamine (61-54-1) → harmane (486-84-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sulfuric acid / water / 0.5 h / 20 °C 1.2: 7 h / Reflux 2.1: maleic acid; palladium on activated charcoal / water / 8 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: sulfuric acid / water / 7 h / Reflux 2: maleic acid; palladium on activated charcoal / water / 8 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: 1,2-dichloro-ethane / 0.05 h / 110 °C / Sealed tube; Microwave irradiation 2: lithium carbonate; 2 mol-% Pd/C / ethanol / 0.17 h / 150 °C / Sealed tube; Microwave irradiation View Scheme

harman-3-carboxylic acid (22329-38-0) → harmane (486-84-0)

Conditions	Yield
With copper In quinoline at 240℃; for 1h;
With sodium hydrogensulfite; sodium hydroxide

C15H15N3O → harmane (486-84-0) + C14H16N2O

Conditions	Yield
With sodium cyanoborohydride In tetrahydrofuran; methanol at 65℃; Inert atmosphere;	A n/a B 20%

trimethylaluminum (75-24-1) + 1-Chlor-9H-pyrido<3,4-b>indol (102337-43-9) → harmane (486-84-0)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; hexane for 3h; Heating;	66%

methyl 5-acetyl-4-[(β-carbolin-1-yl)methyl]-1,4-dihydropyridine-3-carboxylate (668987-16-4) → harmane (486-84-0) + 5-(1'-hydroxyethyl) nicotinic acid methyl ester (38940-64-6) + methyl 4-[(β-carbolin-1-yl)methyl]-5-(1-hydroxyethyl)-1,4-dihydropyridine-3-carboxylate (52811-49-1)

Conditions	Yield
With sodium tetrahydroborate In methanol at 20℃; for 0.25h;

1-(phenylsulfonyl)indole-3-carbaldehyde (80360-20-9) → harmane (486-84-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 63 percent / AcONa; AcOH 2.1: LDA / tetrahydrofuran / 1 h / -78 °C 2.2: tetrahydrofuran / -78 - -10 °C 2.3: 45 percent / NH2OH*HCl; AcONa / 1,2-dichloro-benzene / 8 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: 65 percent / t-BuOK / tetrahydrofuran 2.1: LDA / tetrahydrofuran / 1 h / -78 °C 2.2: tetrahydrofuran / -78 - -10 °C 2.3: 46 percent / NH2OH*HCl; AcONa / 1,2-dichloro-benzene / 8 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: 77 percent / t-BuOK / tetrahydrofuran 2.1: LDA / tetrahydrofuran / 1 h / -78 °C 2.2: tetrahydrofuran / -78 - -10 °C 2.3: 53 percent / NH2OH*HCl; AcONa / 1,2-dichloro-benzene / 8 h / Heating View Scheme

acetaldehyde (75-07-0) + L-Tryptophan (73-22-3) → harmane (486-84-0)

Conditions	Yield
With hydrogenchloride; iron(III) chloride In N,N-dimethyl-formamide at 130℃; for 1h; Catalytic behavior; Pictet-Spengler Synthesis; Green chemistry;	78%
Stage #1: acetaldehyde; L-Tryptophan Acidic conditions; Stage #2: With potassium dichromate
With potassium dichromate

Harman-2-oxide (2506-09-4) → harmane (486-84-0)

Conditions	Yield
With acetic acid; zinc for 2h; Reduction;	87%

Upstream product

• 522-87-2 yohimbinic acid 
• 483-05-6 17α-hydroxy-20α-yohimban-16α-carboxylic acid 
• 7664-93-9 sulfuric acid 
• 75-07-0 acetaldehyde 
• 73-22-3 L-Tryptophan 
• 302-72-7 rac-Ala-OH 
• 525-41-7 1-methyl-4,9-dihydro-3H-β-carboline 
• 487-03-6 harmol 
• 82980-12-9 3-ethenyl-1-phenylsulfonyl-1H-indole 
• 110128-40-0 (E)-1-(Phenylsulfonyl)-3-(β-methoxyvinyl)indole 
• 5159-20-6 1-methyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 
• 942-26-7 5-chlorotryptamine hydrochloride 
• 81868-12-4 2-(5-bromo-1H-indol-3-yl)ethanamine hydrochloride 
• 6678-82-6 (+/-)-Calligonine hydrochloride 

Downstream Products

• 63885-36-9 1-methyl-2-(3-trimethylammonio-propyl)-9H-β-carbolinium; dibromide 
• 63885-34-7 1-methyl-2-(10-trimethylammonio-decyl)-9H-β-carbolinium; dibromide 
• 20127-62-2 (E)-1-(2-phenylvinyl)-9H-pyrido[3,4-b]indole 
• 2506-10-7 eleagnine 
• 102207-02-3 8-nitro-1-methyl-9H-pyrido[3,4-b]indole 
• 38314-91-9 6-nitro-1-methyl-9H-pyrido[3,4-b]indole 
• 15071-56-4 5-methoxycanthin-6-one 
• 64118-73-6 5-hydroxy-canthin-6-one 
• 1229021-11-7 2-(3-phenylpropyl)-1-methyl-β-carbolinium bromide 
• 1229021-10-6 2-benzyl-1-methyl-9H-pyrido[3,4-b]indol-2-ium bromide 
• 1339940-10-1 9-(4-fluorobenzyl)-β-carboline-1-carboxaldehyde 
• 1339940-11-2 9-(3-chlorobenzyl)-β-carboline-1-carboxaldehyde 

Relevant articles and documents

Indole alkaloids from two species of Ophiorrhiza

Extraction of the aerial parts of Ophiorrhiza rosacea Ridley (Rubiaceae) has yielded harman-2-oxide (1). Extraction of the aerial parts of O. kunstleri King yielded the alkaloids palicoside (3) and 3,14-didehydro-19-methylnormalindine (8). The structures

A new method for the synthesis of the marine alkaloid fascaplysin based on the microwave-assisted Minisci reaction

A new two-step method for the synthesis of the marine alkaloid fascaplysin has been developed, via homolytic benzoylation (Minisci reaction) of β-carboline under microwave irradiation followed by intermolecular quaternization.

A convenient synthesis of β-carbolines by iron-catalyzed aerobic decarboxylative/dehydrogenative aromatization of tetrahydro-β-carbolines under air

A convenient synthesis for the conversion of various substituted tetrahydro-β-carbolines has been developed by iron-catalyzed decarboxylative/dehydrogenative aromatization to construct aromatic β-carbolines under air atmosphere. In the presence of a FeCl3 catalyst, this reaction exhibited a good functional group tolerance to produce corresponding β-carbolines in good yields in the absence of any additive. Additionally, the utility of the method was highlighted in the gram-scale synthesis of important natural β-carboline synthons norharmane (2a) and harmane (2b), which the latter provide practical access towards eudistomin N and nostocarboline.

Application of metal free aromatization to total synthesis of perlolyrin, flazin, eudistomin U and harmane

Application of our recently reported metal free reaction conditions to the total synthesis of the four different and selective biologically interesting β-carboline natural products is reported. Using this simple methodology, flazin, perlolyrine, eudistomin U and harmane containing heteroaryl and alkyl substituents at C1 position were synthesized in good yields. (Figure presented.).