1532-97-4Relevant articles and documents
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.
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.
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.
