Sequential SNAr Reactions Research Articles

N1‐Methylthiomethylation of (8‐Aza)6‐Chloropurine with DMSO through the Pummerer Rearrangement

AbstractN1‐[(Methylthio)methyl] hypoxanthines and aza hypoxanthines were efficiently prepared from 6‐chloropurines/azapurines and DMSO under microwave irradiation. DMSO was employed as a readily available and atom‐economic methylthiomethylating reagent and solvent without any other activator. The mechanistic investigations demonstrate that the reaction proceeded via sequential SNAr reaction and the Pummerer rearrangement. The current protocol provides an effective strategy for the synthesis of various N1‐[(methylthio)methyl] (8‐aza)hypoxanthines.

Synthesis of Adagrasib (MRTX849), a Covalent KRASG12C Inhibitor Drug for the Treatment of Cancer

A concise, transition-metal and protection-free synthesis of adagrasib (MRTX849), a novel KRASG12C inhibitor drug recently approved by the FDA, is reported. Introduction of two chiral building blocks to the tetrahydropyridopyrimidine core was accomplished via two sequential SNAr reactions. Extensive reaction optimization led to a robust, transition-metal-free oxidation of the sulfide intermediate. A judicious choice of the leaving group with favorable steric and electronic characteristics at the 4-OH position of the tetrahydropyridopyrimidine core enabled a facile SNAr displacement to introduce the chiral piperazine. This new, five-step, chromatography-free synthesis of adagrasib from readily available starting materials obviated the palladium catalysis and protecting group manipulations in the current commercial route and significantly improved the efficiency of the process in 45% overall yield.

Polyfunctionalized biaryls accessed by a one-pot nucleophilic aromatic substitution and sigmatropic rearrangement reaction cascade under mild conditions

Abstract A practical synthetic method has been developed for polyfunctionalized biaryls based on a facile one-pot nucleophilic aromatic substitution (SNAr) reaction and [5,5]- or [3,3]-sigmatropic rearrangement reaction cascade. Under mild basic conditions, N-arylhydroxylamines reacted with o-activated fluoro (het)arenes to form N,O-diarylhydroxylamine intermediates which underwent spontaneously selective [5,5]-sigmatropic rearrangement reaction to produce diverse functionalized 4-amino-4′-hydroxy-1,1′-biaryls. A sequential SNAr reaction and [3,3]-sigmatropic rearrangement took place between N-arylhydroxylamines and 2-fluoropyridine derivatives or 4-fluorobenzonitrile to afford functionalized 2-amino-2′-hydroxy-1,1′-biaryls. As invaluable and unique building blocks, the resulting biaryls were applied in the straightforward synthesis of N2,O2-coronarene, carbazole, aza- and diaza carbazole derivatives.

Corona[5]arenes Accessed by a Macrocycle-to-Macrocycle Transformation Route and a One-Pot Three-Component Reaction.

Corona[5]arenes, a novel type of macrocyclic compound that is composed of alternating heteroatoms and para-arylenes, were synthesized efficiently by two distinct methods. In a macrocycle-to-macrocycle transformation approach, S6 -corona[3]arene[3]tetrazine underwent sequential SN Ar reactions with HS-C6 H4 -X-C6 H4 -SH (X=S, CH2 , CMe2 , SO2 , and O) to produce the corresponding corona[3]arene[2]tetrazines. Different corona[3]arene[2]tetrazine compounds were also constructed in a straightforward manner by a one-pot three-component reaction of HS-C6 H4 -X-C6 H4 -SH (X=S, CH2 , CMe2 , SO2 , and O) with diethyl 2,5-dimercaptoterephthalate and 2 equiv of 3,6-dichlorotetrazine under very mild conditions. All corona[5]arenes adopted 1,2,4-alternate conformational structures in the crystalline state yielding similar nearly regular pentagonal cavities. Both the cavity size and the electronic property of the acquired macrocycles were fine-tuned by the nature of the bridging element X.

Corona[5]arenes Accessed by a Macrocycle‐to‐Macrocycle Transformation Route and a One‐Pot Three‐Component Reaction

AbstractCorona[5]arenes, a novel type of macrocyclic compound that is composed of alternating heteroatoms and para‐arylenes, were synthesized efficiently by two distinct methods. In a macrocycle‐to‐macrocycle transformation approach, S6‐corona[3]arene[3]tetrazine underwent sequential SNAr reactions with HS‐C6H4‐X‐C6H4‐SH (X=S, CH2, CMe2, SO2, and O) to produce the corresponding corona[3]arene[2]tetrazines. Different corona[3]arene[2]tetrazine compounds were also constructed in a straightforward manner by a one‐pot three‐component reaction of HS‐C6H4‐X‐C6H4‐SH (X=S, CH2, CMe2, SO2, and O) with diethyl 2,5‐dimercaptoterephthalate and 2 equiv of 3,6‐dichlorotetrazine under very mild conditions. All corona[5]arenes adopted 1,2,4‐alternate conformational structures in the crystalline state yielding similar nearly regular pentagonal cavities. Both the cavity size and the electronic property of the acquired macrocycles were fine‐tuned by the nature of the bridging element X.

A complementary route to diaminopyrimidines through regioselective SNAr amination reactions

A novel approach towards the production of diverse sets of diaminopyrimidines through sequential SNAr reactions is reported. The readily prepared 2-chloro-4-tetrafluorophenoxypyrymidine reacts regioselectively with amines at the C-2 position. The tetrafluorophenoxy at C-4 can then be replaced with amines in a second SNAr to afford easy access to a different and complementary set of diaminopyrimidines. The broad utility of this ‘C-2 then C-4’ two-step sequence has been demonstrated with a range of aromatic and aliphatic amines.

An efficient one-pot protocol for asymmetric bifunctionalization of 5,15-disubstituted porphyrins: direct access to meso activated alkenyl-substituted meso-formylporphyrins

An efficient one-pot protocol for the direct conversion of free base 5,15-disubstituted porphyrins into the corresponding meso activated alkenyl-substituted meso-formylporphyrins has been developed using a sequential SNAr reaction with PyMe2SiCH2Li, conjugate addition to enones or alkenoates in the presence of TMSCl, and oxidation with DDQ.

Synthesis of a 2, 4, 8-trisubstituted pyrimidino[5, 4-d]pyrimidine library via sequential SNAr reactions on solid-phase.

A solid-phase synthesis of 2, 4, 8-substituted pyrimidino[5, 4-d]pyrimidines involving three controlled S(N)Ar reactions has been developed. Exploration of different heterocyclic starting materials and resin-bound intermediates is highlighted. The preferred method starts with the treatment of resin-bound anilines with 2, 4, 8-trichloropyrimidino[5, 4-d]pyrimidine. This intermediate is subsequently treated with various amines in two steps to yield the final products. The scope of each diversity step was determined and a library of 16, 000 compounds was synthesized.

Crown-annelated p-phenylenediamine derivatives as electrochemical and fluorescence responsive chemosensors: synthesis via arene–ruthenium chemistry

The synthesis of two crown annelated tetraalkyl-p-phenylenediamine derivatives, via sequential SNAr reactions on (p-dichlorobenzene)RuCp cationic complexes, is described.

Sequential nucleophilic substitution on halogenated triazines, pyrimidines, and purines: a novel approach to cyclic peptidomimetics.

A novel concept for the synthesis of macrocyclic peptidomimetics which incorporate heteroaromatic units is reported. The method involves sequential SNAr reactions of orthogonally protected amino groups of peptides and other linear oligomers on halogenated heterocycles such as 2,4,6-trichloro[1,3,5]triazine, 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine. The scope of this novel solid-phase approach was systematically evaluated by means of the SPOT-synthesis methodology on planar cellulose membranes. Besides the question of the accessibility of different ring sizes and the compatibility with protecting groups of commonly used amino acids, the applicability of the technique toward different halogenated heteroaromatics and peptidomimetics was studied. It was found that the procedure is well suited to assemble a wide variety of cyclic peptidomimetics differing in both size (11- to 37-membered rings) and chemical nature of the assembled backbones.