1532-97-4Relevant academic research and scientific papers
Bromination of isoquinoline, quinoline, quinazoline and quinoxaline in strong acid
Brown,Gouliaev
, p. 83 - 86 (2002)
Bromination of benzazines and benzodiazines most often gives a mixture of products. In this paper, we show that isoquinoline (1) may be regioselectively monobrominated in concentrated H2SO4 using NBS or in CF3SO3H using N,N′-dibromoisocyanuric acid (DBI) to give 5-bromoisoquinoline (2). The bromination was found to be highly sensitive to the choice of brominating agent, acid, temperature and concentration. Quinoline, quinazoline and quinoxaline may be brominated likewise, although with the strong regioselectivity reserved to isoquinoline.
Predictable site-selective functionalization: Promoter group assistedpara-halogenation ofN-substituted(hetero)aromatics under metal-free condition
Gupta, Shiv Shankar,Manisha,Kumar, Rakesh,Dhiman, Ankit Kumar,Sharma, Upendra
, p. 9675 - 9687 (2021/12/01)
Herein, regioselectivepara-C-H halogenation ofN-pyrimidyl (hetero)aromatics through SEAr (electrophilic aromatic substitution) type reaction is disclosed. SEAr type reaction has been utilized for the C5-bromination of indolines (para-selective) withN-bromosuccinimide under metal and additive-free conditions in good to excellent yields. The developed methodology is also applicable for iodination and challenging chlorination. The pyrimidyl group is identified as a reactivity tuner that also controls the regioselectivity. The present method is also applicable for selective halogenation of aniline, pyridine, indole, oxindole, pyrazole, tetrahydroquinoline, isoquinoline, and carbazole. DFT studies such as Fukui nucleophilicity and natural charge maps also support the observedp-selectivity. Post-functionalization of the title compound into the corresponding arylated, olefinated, and dihalogenated products is achieved in a one-pot, two-step fashion. Late-stage C-H bromination was also executed on drug/natural molecules (harmine, etoricoxib, clonidine, and chlorzoxazone) to demonstrate the applicability of the developed protocol.
Preparation method of 4-halogenated isoquinoline compound
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Paragraph 0025-0027, (2021/08/19)
The invention relates to a preparation method of a 4-halogenated isoquinoline compound. The method comprises the following steps: adding an Ag2O catalyst, a reactant I, a reactant II, a K2S2O8 oxidant, an acetonitrile solution and magneton into a reactor, placing the reactor in an oil bath pan with the temperature of 60-100 DEG C, heating and reacting for 4-12 hours, pouring the reaction liquid into a separating funnel, adding distilled water, extracting with ethyl acetate, merging the obtained organic phases, carrying out rotary drying by using a rotary evaporator, and carrying out column chromatography separation and purification on a crude product to obtain the 4-halogenated isoquinoline compound, wherein the reactant I is isoquinoline; and the reactant II is KX, and X is halogen. The 4-halogenated isoquinoline compound is synthesized by taking an isoquinoline group as a positioning group and carrying out halogenation reaction at the No.4 site of isoquinoline. The method is mild in reaction condition, relatively high in yield and environment-friendly. Through detection, the synthesized 4-halogenated isoquinoline compound has better biological activity and can be applied to the fields of drug synthesis, pesticide synthesis, paint dye synthesis and the like.
Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes
Fosu, Stacy C.,Hambira, Chido M.,Chen, Andrew D.,Fuchs, James R.,Nagib, David A.
supporting information, p. 417 - 428 (2019/02/14)
Fosu, Hambira, and colleagues describe the direct C–H functionalization of medicinally relevant arenes or heteroarenes. This strategy is enabled by transient generation of reactive, non-symmetric iodanes from anions and PhI(OAc)2. The site-selective incorporation of Cl, Br, OMs, OTs, and OTf to complex molecules, including within medicines and natural products, can be conducted by the operationally simple procedure included herein. A computational model for predicting site selectivity is also included. The discovery of new medicines is a time- and labor-intensive process that frequently requires over a decade to complete. A major bottleneck is the synthesis of drug candidates, wherein each complex molecule must be prepared individually via a multi-step synthesis, frequently requiring a week of effort per molecule for thousands of candidates. As an alternate strategy, direct, post-synthetic functionalization of a lead candidate could enable this diversification in a single operation. In this article, we describe a new method for direct manipulation of drug-like molecules by incorporation of motifs with either known pharmaceutical value (halides) or that permit subsequent conversion (pseudo-halides) to medicinally relevant analogs. This user-friendly strategy is enabled by combining commercial iodine reagents with salts and acids. We expect this simple method for selective, post-synthetic incorporation of molecular diversity will streamline the discovery of new medicines. A strategy for C–H functionalization of arenes and heteroarenes has been developed to allow site-selective incorporation of various anions, including Cl, Br, OMs, OTs, and OTf. This approach is enabled by in situ generation of reactive, non-symmetric iodanes by combining anions and bench-stable PhI(OAc)2. The utility of this mechanism is demonstrated via para-selective chlorination of medicinally relevant arenes, as well as site-selective C–H chlorination of heteroarenes. Spectroscopic, computational, and competition experiments describe the unique nature, reactivity, and selectivity of these transient, unsymmetrical iodanes.
CANNABINOID RECEPTOR MODULATORS
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Page/Page column 40, (2013/03/26)
Compounds of Formula (I) along with processes for their preparation that are useful for treating, managing and/or lessening the diseases, disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors. Methods of treating, managing and/or lessening the diseases, disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors of Formula (I).
1,2-Dihydroisoquinoline-N-acetic acid derivatives as new carriers for brain-specific delivery II: Delivery of phenethylamine as model drug
Mahmoud, Sahar,Sheha, Mahmoud,Aboul-Fadl, Tarek,Farag, Hassan
, p. 258 - 263 (2007/10/03)
N-alkyloxycarbonylmethyl-1,2-dihydroisoquinolin-4-carboxylic acid derivatives 7 a-c were synthesized as new carriers for brain specific delivery. The design of the carrier systems are based on sequential hydrolysis at the acetic acid ester group linked to dihydroisoquinoline nitrogen followed by ring oxidation and formation of quaternary isoquinolinium derivatives which are then hydrolyzed to release the drug. Once the carrier system is administered, a sequential enzymatic process will take place resulting in significant increase in its rate of oxidation, the key factor in brain specific delivery. The chemical stability of the synthesized carrier system was investigated in aqueous buffer solutions and ferricyanide reagent and proofed to be quite stable against hydration and oxidation during formulation and storage. Furthermore, enzymatic stability was also investigated in 80% human plasma and 20% rabbit brain homogenate. Both oxidation and hydrolysis were found to take place; however, hydrolysis was the major route. In vivo distribution of the ethyl ester derivative 7 b was studied in rats and showed that the concentration of the quaternary product is increasing in the brain and cleared from blood with time.
Solvolyses of 2-Deoxy-α- and β-D-Glucopyranosyl 4′-Bromoisoquinolinium Tetrafluoroborates
Zhu, Jiang,Bennet, Andrew J.
, p. 4423 - 4430 (2007/10/03)
The solvolyses of 2-deoxy-α- and β-D-glucopyranosyl 4′-bromoisoquinolinium tetrafluoroborates (1 and 2) were monitored in aqueous methanol, ethanol, trifluoroethanol, and binary mixtures of ethanol and trifluoroethanol. The observed rate constants are consistent with the solvolyses of 1 and 2 proceeding via dissociative (DN * AN) transition states. In comparison to the α-anomer, solvolysis of the β-compound gives a greater transition state charge delocalization onto the ring oxygen atom. Analysis of the solvolysis product ratios indicates that the 2-deoxyglucosyl oxacarbenium ion is not solvent-equilibrated in the solvent mixtures studied. In the solvolysis of compound 1, the solvent trifluoroethanol facilitates diffusional separation of the leaving group and, in so doing, promotes the formation of the retained trifluoroethyl glycoside.
Hydrolysis of (2-deoxy-α-D-glucopyranosyl)pyridinium salts: The 2- deoxyglucosyl oxocarbenium is not solvent-equilibrated in water
Zhu, Jiang,Bennet, Andrew J.
, p. 3887 - 3893 (2007/10/03)
The hydrolysis reactions of four 2-deoxy-α-D-glucopyranosyl pyridinium salts exhibit first-order rate constants that are independent of pH in the range of 4.4-10.5 pH units. Derived second-order rate constants for the hydrolysis reactions of 2-deoxy-α-D-glucopyranosyl 4'-bromoisoquinolinium tetrafluoroborate (4d) conducted in the presence of nucleophilic monoanions (u = 2.0) including AcO-, Cl-, Br-, and N3/- exhibit a Swain-Scott parameter (s) of 0.03 ± 0.10, indicating that these reactions show no sensitivity to the nature of the anion. In the presence of azide ion, a substantial quantity of the 2-deoxy-α-glucopyranosyl 4'-bromoisoquinolinium salt hydrolysis product results from a post rate-limiting reaction of a cationic intermediate with azide. Analysis of the hydrolysis product ratios indicates that the 2-deoxyglucosyl oxocarbenium ion is not solvent- equilibrated in water. Furthermore, the reaction of solvent occurs about 2- fold faster with the cationic intermediate that is formed during solvolysis of the β-anomeric salt than with the corresponding intermediate produced from the reactions of the α-anomer 4d.
Microbial deoxygenation of N-oxides with Baker's yeast-NaOH
Baik, Woonphil,Kim, Dong Ik,Koo, Sangho,Rhee, Jong Uk,Shin, Sung Hee,Kim, Byeong Hyo
, p. 845 - 848 (2007/10/03)
The microbial deoxygenation of a series of aromatic and heteroaromatic N-oxide compounds, including quinoline N-oxides, isoquinoline N-oxides, 2-aryl-2H-benzotriazole 1-oxides, benzo[c]cinnoline N-oxide and azoxybenzenes, has been performed with bakers'yeast-NaOH.
Hydrolysis of (2-deoxy-β-D-glucopyranosyl)pyridinium salts
Huang, Xicai,Surry, Clint,Hiebert, Timothy,Bennet, Andrew J.
, p. 10614 - 10621 (2007/10/03)
The hydrolysis reactions of three (2-deoxy-β-D-glucopyranosyl)pyridinium salts exhibit first-order rate constants that are independent of pH in the range of 4.4-10.1 pH units. Derived second-order rate constants for the hydrolysis reactions of (2-deoxy-β-D-glucopyranosyl)-4′-bromoisoquinolinium bromide (5b) conducted in the presence of nucleophilic monoanions (μ = 2.0) including AcO-, Cl-, Br-, and N3 exhibit a Swain-Scott parameter (s) of 0,03 ± 0.05, indicating that these reactions show no sensitivity to the nature of the anion. However, a substantial quantity of the (2-deoxyglucopyranosyl)pyridinium salt hydrolysis product is formed as a result of a post-rate-limiting reaction involving a nucleophilic anion. Analysis of the product ratios indicates that the first-formed intermediate in the hydrolytic reaction is a solvent-separated ion painmolecule encounter complex. The data allow a calculated estimate of greater than 2.5 × 10-12 s for the lifetime of the glucopyranosyloxocarbenium ion in aqueous solution.
