2620-13-5Relevant articles and documents
Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines
Cheng, Jiang-Tao,Dong, Xiao-Yang,Gu, Qiang-Shuai,Li, Zhong-Liang,Liu, Juan,Liu, Xin-Yuan,Luan, Cheng,Wang, Fu-Li,Wang, Li-Lei,Yang, Ning-Yuan,Zhang, Yu-Feng
supporting information, p. 15413 - 15419 (2021/09/30)
α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenrichedN-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.
Silver-Catalyzed Chemoselective [4+2] Annulation of Two Isocyanides: A General Route to Pyridone-Fused Carbo- and Heterocycles
Hu, Zhongyan,Dong, Jinhuan,Men, Yang,Lin, Zhichen,Cai, Jinxiong,Xu, Xianxiu
supporting information, p. 1805 - 1809 (2017/02/05)
A silver-catalyzed chemoselective [4+2] annulation of aryl and heteroaryl isocyanides with α-substituted isocyanoacetamides was developed for the facile and efficient synthesis of 2-aminoquinolones, naphthyridines, and phenanthrolines. A mechanism for this multistep domino reaction is proposed on the basis of a13C-labeling experiment, according to which an unprecedented chemoselective heterodimerization of two different isocyanides generates an α-amidoketenimine intermediate, which undergoes 1,3-amino migration to form an α-imidoylketene, followed by 6 π electrocyclization.
Antinociceptive (Aminoalkyl)indoles
Bell, Malcolm R.,D'Ambra, Thomas E.,Kumar, Virendra,Eissenstat, Michael A.,Herrmann, John L.,et al.
, p. 1099 - 1110 (2007/10/02)
The (aminoalkyl)indole (AAI) derivative pravadoline (1a) inhibited prostaglandin (PG) synthesis in mouse brain microsomes in vitro and ex vivo and exhibited antinociceptive activity in several rodent assays.In vitro structure-activity relationship studies of this new class of PG synthesis inhibitors revealed a correspondence in three respects to those reported for the arylacetic acids: (1) "α-methylation" caused an increase in PG inhibitory potency, (2) the (R)-α-methyl isomer was more active than the S isomer, (3) the hypothesized aroyl group conformation of the 2-methyl derivatives corresponded to the proposed and reported "active" conformations of the aroyl and related aromatic acetic acid derivatives.The 1H NMR chemical shift of the C-4 hydrogen of pravadoline in comparison to the deshielding seen with 50, which lacks a substituent at C-2, suggested that the carbonyl group of pravadoline is located near C-2 but is located near C-4 in 50.Associated with this conformational change of the carbonyl group of 1a is a diminution of PG synthetase inhibitory activity.The results of UV and difference nuclear Overhauser studies of the two compounds were consistent with these conformational assignments.The low eudismic ratios of the α-methyl derivatives and the observation that the side chain may be extended by three methylene groups without significant loss of PG inhibitory potency suggests that this class of inhibitors bound less strongly and less selectively to the active site of PG synthetase than do the arylacetic acids.Two AAIs, 1a and 30, were found to be metabolized to the corresponding acetic acid derivatives, both of which inhibited PG synthesis.An exception to the observation that the antinociceptive activity of the AAIs was associated with PG synthetase inhibitory activity was the 1-naphthoyl derivative 67 since neither it nor its acetic acid metabolite 74 inhibited PG synthesis.Yet 67 was antinociceptive in four different rodent assays.This naphthoyl derivative, like opioids, also inhibited electrically stimulated contractions in the mouse vas deferens (MVD) preparation.Unlike opioids, however, the inhibition was not antagonized by naloxone.A subseries of AAIs was identified, of which 67 was prototypic.These compounds lacked PG synthetase inhibitory activity, but their inhibitory potency in MVD preparations correlated roughly with their antinociceptive potency in vivo.Pravadoline was also inhibitory in MVD.Is antinociceptive activity, therefore, may be a consequence of both its PG synthease inhibitory potency and another antinociceptive mechanism, the latter associated with its inhibitory potency in the MVD.The evidence is summarized which suggests that this second antinociceptive mechanism is associated with binding to the recently characterized cannabinoid receptor.
