2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines

doi:10.1016/0040-4039(95)01316-A

Tetrahedron Letters

Volume 36, Issue 36, 4 September 1995, Pages 6373-6374

https://doi.org/10.1016/0040-4039(95)01316-A Get rights and content

Abstract

2- and 4-Nitrobenzenesulfonamides, readily prepared from primary amines, undergo smooth alkylation by Mitsunobu reaction or by conventional methods to give N-alkylated sulfonamides in near quantitative yields. These sulfonamides could be deprotected readily via Meisenheimer complexes upon treatment with thiolates in DMF at room temperature, giving secondary amines in high yields.

Graphic

References (6)

J.R. Henry et al.
Tetrahedron Lett.
(1989)
S.R. Sandler et al.
Organic Functional Group Preparations
(1983)
T. Tsunoda et al.
Chem. Lett.
(1994)

There are more references available in the full text version of this article.

Cited by (933)

Fluorinated 2,6-Xylenesulfonyl Group: A Protective Group for Amines
2023, Organic Letters
Synthesis of 1-Deoxymannojirimycin from d -Fructose using the Mitsunobu Reaction
2022, Journal of Organic Chemistry
Three different Mitsunobu reactions have been investigated for the synthesis of 1-deoxymannojirimycin (1-DMJ) from d-fructose. The highest yielding and most practical synthesis can be undertaken on a 10 g scale with minimal chromatography. In the key step, N,O-di-Boc-hydroxylamine reacts with methyl 1,3-isopropylidene-α-d-fructofuranose under Mitsunobu conditions to give 14. Acidic hydrolysis affords nitrone 15, which reduces quantitatively via catalytic hydrogenolysis to afford 1-DMJ (4) in 55% overall yield from d-fructose (cf. 37% for azide route and 29% for nosyl route).
Symmetric lipophilic polyamines exhibiting antitumor activity
2022, Bioorganic and Medicinal Chemistry
Unsymmetric lipophilic polyamine derivatives are considered as potential antitumor agents. Here, a series of novel symmetric lipophilic polyamines (LPAs) based on norspermine and triethylenetetramine (TETA) backbones bearing alkyl substituents with different lengths (from decyl to octadecyl) at C(1) atom of glycerol were synthesized. Performed screening of the cytotoxicity of novel compounds on the panel of tumor cell lines (MCF-7, KB-3-1, B16) and non-malignant fibroblasts hFF3 in vitro revealed a correlation between the length of the aliphatic moieties in LPAs and their toxic effects – LPAs with the shortest decyl substituent were found to exhibit the highest cytotoxicity. Furthermore, norspermine-based LPAs displayed somewhat more pronounced cytotoxicity compared with their TETA-based counterparts. Further mechanistic studies demonstrated that hit LPAs containing the norspermine backbone and tetradecyl or decyl substituents efficiently induced apoptosis in KB-3-1 cells. Moreover, decyl-bearing LPA inhibited motility and enhanced adhesiveness of murine B16 melanoma cells in vitro, showing promising antimetastatic potential. Thus, developed novel symmetric norspermine-based LPAs can be considered as promising anticancer chemotherapeutic candidates.
Discovery of potent indazole-based human glutaminyl cyclase (QC) inhibitors as Anti-Alzheimer's disease agents
2022, European Journal of Medicinal Chemistry
Citation Excerpt :
Commercially available 6-nitroindazole (24) was protected with a Boc group or N-alkylated with different alkyl halides to provide the corresponding 1-alkylated indazoles (25–27). The N-substituted anilines of the indazole derivatives were synthesized by either reductive amination or treatment with 2-nitrobenzenesulfonamide to prepare secondary amines, as shown in Scheme 2 [59,60]. The nitro groups of the synthesized 5/6-nitro indazole derivatives in Scheme 1 were converted into the corresponding amines (28–40) by catalytic hydrogenation.
The toxic pyroglutamate form of amyloid-β (pE-Aβ) is important for the pathogenesis of early Alzheimer's disease (AD); therefore, reducing pE-Aβ by inhibiting glutaminyl cyclase (QC) provides a promising strategy for developing disease-modifying AD drugs.
In this study, potent and selective QC inhibitors with desirable drug-like properties were discovered by replacing the 3,4-dimethoxyphenyl group in a QC inhibitor with a bioisosteric indazole surrogate. Among them, 3-methylindazole-6-yl and 3-methylindazole-5-yl derivatives with an N-cyclohexylurea were identified as highly potent inhibitors with IC₅₀ values of 3.2 nM and 2.3 nM, respectively, both of which were approximately 10-fold more potent than varoglutamstat. In addition, the three inhibitors significantly reduced pE-Aβ_3-40 levels in an acute animal model after intracerebroventricular (icv) injection and were selective for hQC. Further in vitro pharmacokinetic and toxicity studies, including those investigating cytotoxicity, hERG inhibition, blood–brain barrier (BBB) permeability and metabolic stability, indicated that N-(3-methylindazole-6-yl)-N’-(cyclohexyl)urea derivative exhibited the most promising efficacy, selectivity and drug-like profile; thus, it was evaluated for its in vivo efficacy in an AD model.
Asymmetric Total Synthesis of All Rugulovasine Stereoisomers and Preliminary Evaluation of Their Biological Properties
2022, European Journal of Organic Chemistry
A unified enantioselective synthesis and the biological evaluation of all rugulovasine stereoisomers are reported. The syntheses are centered on the divergent and stereochemical modular combination of each enantiomer of 4‐amino Uhle's ketone and a methacrylate derivative to build the unsaturated oxaspirolactone moiety by the Dreiding‐Schmidt reaction, followed by Fukuyama alkylation to afford the required N‐methyl secondary amine in excellent yield. The modularity of this divergent approach, the diastereoselectivities of the reactions, and the late‐stage site‐selective methylation permit the rapid asymmetric syntheses of all rugulovasine stereoisomers, including the first total syntheses of optically pure (+)‐ and (−)‐rugulovasine B and their trideuteromethylated derivatives. All enantiopure stereoisomers of rugulovasine were tested for their binding affinities to dopamine, serotonin, and adrenergic neuroreceptors, revealing their preferred selectivity for the serotonin 1 A receptor.
Second-generation DNA-encoded multiple display on a constant macrocyclic scaffold enabled by an orthogonal protecting group strategy
2022, Chinese Chemical Letters
DNA-encoded chemical library (DEL) represents an emerging drug discovery technology to construct compound libraries with abundant chemical combinations. While drug-like small molecule DELs facilitate the discovery of binders against targets with defined pockets, macrocyclic DELs harboring extended scaffolds enable targeting of the protein–protein interaction (PPI) interface. We previously demonstrated the design of the first-generation DNA-encoded multiple display based on a constant macrocyclic scaffold, which harvested binders against difficult targets such as tumor necrosis factor-α (TNF-α). Here, we developed a novel strategy which utilized four orthogonal amine-protecting groups on DNA, to explore larger chemical combinations on the same constant macrocyclic scaffold, following the parallel paradigm to mimic the versatile antibody-like multivalent epitope recognition patterns. We successfully integrated these orthogonal protecting groups with acylation and made a mock second-generation DNA-encoded display combination. This work illustrates a strategy to produce larger encoded multiple display on a constant macrocyclic scaffold, which could facilitate potential binder discovery with enhanced affinity to clinically significant PPI targets.

View all citing articles on Scopus

¹: Address correspondence to this author at Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.

View full text

2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines

Abstract

Tetrahedron Lett.

Organic Functional Group Preparations

Chem. Lett.