486-84-0

Usage

Uses

Used in Trace Level Determination:
Harmane is used as a trace level determinant by planar chromatography coupled with tandem mass spectrometry for its analysis.
Used in DNA Interaction Studies:
Harmane is utilized in studying the interactions of norharman and harman with DNA, which can provide insights into its biological effects and potential applications.
Used in Analysis of Cyclodextrins:
Harmane serves as a matrix for the analysis of cyclodextrins, which are important in various chemical and pharmaceutical applications.
Used in Sulfated Oligosaccharides Analysis:
In combination with DHB as a co-matrix, harmane is used for the analysis of sulfated oligosaccharides, which have potential applications in the development of new drugs and therapies.
Used in Pharmaceutical Industry:
Harmane, due to its inhibitory effects on monoamine oxidase A, can be explored for its potential use in the development of pharmaceuticals targeting neurological disorders and other conditions related to monoamine oxidase A activity.
Used in Toxicology and Environmental Studies:
As a potent neurotoxin and a member of heterocyclic aromatic amines, harmane can be studied in toxicology and environmental research to understand its effects on human health and the environment, as well as to develop methods for its detection and mitigation.

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

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

• 2506-10-7 eleagnine 
• 31965-09-0 1-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-b]indole 
• 487-03-6 harmol 
• 73-22-3 L-Tryptophan 
• 522-87-2 yohimbinic acid 
• 483-05-6 17α-hydroxy-20α-yohimban-16α-carboxylic acid 
• 146-48-5 Yohimbine 
• 75-07-0 acetaldehyde 
• 54-12-6 Trp 
• 7732-18-5 water 
• 2506-09-4 Harman-2-oxide 
• 525-41-7 1-methyl-4,9-dihydro-3H-β-carboline 
• 5470-37-1 1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid 
• 5159-20-6 1-methyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 

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 
• 96405-70-8 picrasidine L 
• 18203-05-9 3-chloro-1-methyl-9H-pyrido[3,4-b]indole 
• 18813-71-3 6-bromo-1-methyl-9H-pyrido[3,4-b]indole 
• 144434-73-1 8-bromo-1-methyl-9H-pyrido[3,4-b]indole 
• 144434-75-3 1-methyl-6,8-dibromo-β-carboline 
• 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 

Relevant academic research and scientific papers

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

β-Carboline Alkaloids 9 [1]. Total Synthesis of the β-Carboline Alkaloids Arenarine A and (±)Arenarine B

The first total synthesis of the β-carboline alkaloids arenarine A (1) and arenarine B (2) is described. Methanolysis of the α-bromoketone 9 gives 1 in good yield. Alternatively 1 can be obtained from the diazoketone 11 with boron trifluoride/methanol in poor yield. Reduction of 1 with sodium borohydride gives racemic arenarine B (2). Regioselective homolytic methylation of norharmane (4) with tert-butyl hydroperoxide/ferrous sulfate gives the alkaloid harmane (6).

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.

Visible light mediated selective oxidation of alcohols and oxidative dehydrogenation of N-heterocycles using scalable and reusable La-doped NiWO4nanoparticles

Visible light-mediated selective and efficient oxidation of various primary/secondary benzyl alcohols to aldehydes/ketones and oxidative dehydrogenation (ODH) of partially saturated heterocycles using a scalable and reusable heterogeneous photoredox catalyst in aqueous medium are described. A systematic study led to a selective synthesis of aldehydes under an argon atmosphere while the ODH of partially saturated heterocycles under an oxygen atmosphere resulted in very good to excellent yields. The methodology is atom economical and exhibits excellent tolerance towards various functional groups, and broad substrate scope. Furthermore, a one-pot procedure was developed for the sequential oxidation of benzyl alcohols and heteroaryl carbinols followed by the Pictet-Spengler cyclization and then aromatization to obtain the β-carbolines in high isolated yields. This methodology was found to be suitable for scale up and reusability. To the best of our knowledge, this is the first report on the oxidation of structurally diverse aryl carbinols and ODH of partially saturated N-heterocycles using a recyclable and heterogeneous photoredox catalyst under environmentally friendly conditions.

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.

Molecular hybrid design, synthesis, in vitro and in vivo anticancer evaluation, and mechanism of action of N-acylhydrazone linked, heterobivalent β-carbolines

A series of N-acylhydrazone-linked, heterobivalent β-carboline derivatives was designed and synthesized from L-tryptophan in a nine-step reaction sequence. The effort resulted in the heterobivalent β-carbolines 10a–t in good yields. The target compounds were characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). The in vitro cytotoxic activity of the synthesized compounds was evaluated against normal EA.HY926 cells and five cancer cell lines: LLC (Lewis lung carcinoma), BGC-823 (gastric carcinoma), CT-26 (murine colon carcinoma), Bel-7402 (liver carcinoma), and MCF-7 (breast carcinoma). Compound 10e, with an IC50 value of 2.41 μM against EA.HY926 cells, was the most potent inhibitor. It showed cytotoxicity against all five cancer cell lines of different origin – murine and human, with IC50 values ranging from 4.2 ± 0.7 to 18.5 ± 3.1 μM. A study of structure-activity relationships indicated that the influence on cytotoxic activities of the substituent in the R9′-position followed the tendency, 2,3,4,5,6-perfluorophenylmethyl > 4-fluorobenzyl > 3-phenylpropyl group. The antitumor efficacies of the selected compounds were also evaluated in mice. Compound 10e exhibited potent antitumor activity, with tumor inhibition of more than 40% for Sarcoma 180 and 36.7% for Lewis lung cancer. Furthermore, the pharmacological mechanisms showed that compound 10e has a certain impairment in the motility of LLC cells, which suggests the anti-metastatic potential. And compound 10e inhibited angiogenesis in chicken chorioallantoic membrane assay, and the anti-angiogenetic potency was more potent than the reference drug combretastatin A4-phosphate (CA4P) at a concentration 50 μM.

Preparation method and application of 6-substituted-beta-carboline alkali compound and derivative

The invention relates to a preparation method and application of a 6-substituted-beta-carboline alkali compound and a derivative. The invention discloses a novel compound, namely the 6-substituted-beta-carboline alkali compound, and an application of the 6-substituted-beta-carboline alkali compound in a farm chemical bactericide. The invention also discloses the preparation method of the 6-substituted-beta-carboline alkali compound. The 6-substituted-beta-carboline alkali compound disclosed by the invention is a novel compound, has relatively good antibacterial activity and can be applied to farm chemical bactericides.

Compound and preparation method and application thereof

The invention relates to the field of anticancer and analgesic drugs. The present invention provides compounds useful for the preparation of cancer treatment and analgesic agents. The invention also provides a preparation method of the compound. The synthesis method provided by the invention is simple to operate, has universality and is suitable for batch production. The invention provides an application of the compound in preparation of drugs for treating cancers and pains. The medicine prepared from the compound can effectively resist cancer and reduce dependence on opioid medicines in cancer pain treatment, and a good pain management mechanism is established.

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.).

Simultaneous generation of acrylamide, β-carboline heterocyclic amines and advanced glycation ends products in an aqueous Maillard reaction model system

The simultaneous formation of acrylamide; β-carboline heterocyclic amines (HAs): harmane and norharmane; and advanced glycation end products (AGEs) (Nε-(carboxymethyl)lysine (CML) and Nε-(carboxyethyl)lysine (CEL)) was analyzed based on an aqueous model system. The model systems included lysine–glucose (Lys/Glu), asparagine–glucose (Asn/Glu), tryptophan–glucose (Trp/Glu), and a mixture of these amino acids (Mix/Glu). Only AGEs were generated when heated at 100 °C, Asn and Trp competed with Lys for glucose and methylglyoxal (MGO), and glyoxal (GO) decreased AGE content. The k value of CML, CEL, and acrylamide decreased when heated at 130 °C, whereas that of harmane increased in the Mix/Glu, owing to the competition between Lys and Asn for glucose, GO, and MGO. Harmane preferably formed via the Pictet–Spengler condensation between Trp and acetaldehyde, which further reduced acrylamide formation via the acrolein pathway.