Intramolecular SNAr Research Articles

TMSNEt2-Promoted Intramolecular SNAr Reaction of Electron-Rich Aryl Fluorides

TMSNEt2-Promoted Intramolecular SNAr Reaction of Electron-Rich Aryl Fluorides

One-Pot Synthesis of N-Fused Quinolone-4 Tetracyclic Scaffolds from 2,2-Disubstituted Indolin-3-ones.

A cascade transformation of C2-quaternary indoxyls leading to an efficient assembly of complex (dihydro)indolo[1,2-a]quinolin-5-one ring systems is reported. The method involves the gram-scale preparation of 2-(2-aryl-3-oxoindolin-2-yl)-2-phenylacetonitriles which are then converted with methyl ketones to the corresponding 2-(2-oxo-2-aryl(alkyl)ethyl)-2-phenylindolin-3-ones. The latter can either be isolated with good yields (75-96%) or, in the case of o-nitroacetophenone, used in situ for further base-assisted intramolecular SNAr cyclization resulting in indoxyl-fused quinolone-4 hybrids (up to 95%).

Metal-free internal nucleophile-triggered domino route for synthesis of fused quinoxaline [1,4]-diazepine hybrids and the evaluation of their DNA binding properties

An unprecedented metal-free synthesis of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine hybrids have been reported under mild conditions through a domino intermolecular SNAr followed by an internal nucleophile-triggered intramolecular SNAr pathway. Our strategy offers the flexibility for the introduction of a broad variety of functionalities at the N-1 position of fused diazepine moiety by using suitable diamine tails to design structurally diverse scaffolds. The DNA binding properties of representative quinoxaline diazepine hybrids were studied using UV–vis absorbance and EtBr displacement assay and were found to be governed by the functionalities at the N-1 position. Interestingly, compound 11f containing the N-1 benzyl substitution demonstrated significant DNA binding (KBH ∼ 2.15 ± 0.25 × 104 M−1 and Ksv ∼ 12.6 ± 1.41 × 103 M−1) accompanied by a bathochromic shift (Δλ ∼ 5 nm). In silico studies indicated possible binding of diazepine hybrid 11f at the GC-rich major groove in the ct-DNA hexamer duplex and showed comparable binding energies to that of ethidium bromide. The antiproliferative activity of compounds was observed in the given order in different cell lines: (HeLa > HT29 > SKOV 3 > HCT116 > HEK293). Lead compound 11f demonstrated maximum cytotoxicity (IC50 value of 13.30 μM) in HeLa cell lines and also caused early apoptosis-mediated cell death in cancer cell lines. We envision that our work will offer newer methodologies for the construction of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine class of molecules.

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4'-piperidine] Building Block.

An efficient and scalable route to tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor GDC-1971 (migoprotafib), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by n-butyllithium, participated in umpolung reactivity via 1,2-addition to tert-butyl 4-oxopiperidine-1-carboxylate (N-Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures. Treatment of the resulting tetrahedral intermediate with oxalic acid resulted in collapse to the corresponding 4-(2-fluorobenzoyl)-4-hydroxypiperidine, which was isolated as a solid via crystallization. The synthesis concluded with an optimized intramolecular SNAr reaction and final crystallization to generate tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate as a stable, high-quality intermediate suitable for further functionalization toward GDC-1971.

Adventures in the Chemistry of Nitro Compounds

AbstractThe present article provides an overview of our work related to cyclization reactions of nitro-substituted electrophilic building blocks with various nucleophiles. As electrophiles, we used nitro-substituted benzoylacetones, 3-ethoxy-2-nitro-2-en-1-ones, 2-nitrobenzoyl chlorides, 4-chloro-3-nitrocoumarin, 2-nitromalonic aldehyde, 3-nitrochromone and 1-(2-chloro-5-nitrophenyl)prop-2-yn-1-ones. As nucleophiles, 1,3-dicarbonyl compounds, 1,3-bis(silyloxy)-1,3-butadienes, (heterocyclic) enamines, hydroxylamine, hydrazines, amines and amino esters were employed. The products include a variety of nitro-substituted carbo- and heterocycles that are not readily available by other methods. The electron-withdrawing nitro group can be easily transformed into an electron-donating amino group which is not only pharmacologically relevant, but can also act as a nucleophile in inter- and intramolecular reactions with electrophiles, such as aldehydes, and can be converted into other functional groups. The nitro group has the capacity to activate compounds for regioselective palladium-catalyzed CH-arylation reactions. Inter- and intramolecular CH arylations of nitro-substituted heterocyclic building blocks, such as 4-nitropyrazoles, 4-nitroimidazoles, 2-nitroindole and nitro-substituted purine analogues, allow for a convenient diversity-oriented approach to the corresponding arylated products. In addition, the nitro group can act as a leaving group in SNAr reactions. Various fused benzofuro[3,2-b]pyridines were prepared by intramolecular SNAr reactions of 2-(hydroxyphenyl)-3-nitropyridines.1 Introduction2 Cyclizations of 1,3-Bis(silyloxy)-1,3-butadienes3 Cyclizations of Heterocyclic Enamines4 Reactions of Simple Nitro-Substituted Heterocycles5 Hydroamination Reactions of Alkynes6 Miscellaneous7 Conclusions

Synthesis of benzimidazole-fused 1,4-benzoxazepines and benzosultams spiro-connected to a 2-oxindole core via a tandem epoxide-opening/SNAr approach.

While hundreds of literature reports describe the preparation of spirooxindole-based five- and six-membered heterocycles, the construction of seven-membered heterocyclic rings spiro-connected to a 2-oxindole core has so far been less developed. Herein, we disclose a base-mediated (4 + 3) annulation of spiro-epoxyoxindoles and 2-(2-fluoroaryl)-1H-benzoimidazoles or 2-fluoro-N-arylbenzenesulfonamides toward the synthesis of two new classes of spirooxindole-based polycyclic systems. Mechanistically, this conceptually simple and high atom-economical reaction proceeds via an SN2-like intermolecular epoxide ring-opening, accompanied by a concomitant intramolecular SNAr reaction. From a synthetic aspect, the notable features of the process are its full regioselectivity, operational simplicity using readily available substrates under transition-metal-free conditions, high yields, and broad substrate scope.

De novo synthesis of inherently chiral heteracalix[4]aromatics from enantioselective macrocyclization enabled by chiral phosphoric acid-catalyzed intramolecular SNAr reaction

N3,O-calix[2]arene[2]triazines, whose inherent chirality arises from one different heteroatom linkage, were synthesized enantioselectively in ee up to 95% from macrocyclization via chiral monophosphoric acid-catalyzed intramolecular SNAr reaction.

Modular, automated synthesis of spirocyclic tetrahydronaphthyridines from primary alkylamines

Spirocyclic tetrahydronaphthyridines (THNs) are valuable scaffolds for drug discovery campaigns, but access to this 3D chemical space is hampered by a lack of modular and scalable synthetic methods. We hereby report an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines (“1,8-THNs”), in addition to their regioisomeric 1,6-THN analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated vinylpyridines is sequenced in combination with intramolecular SNAr N-arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a palladium-catalysed C–N bond formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting materials, using the same bond disconnections. The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core of Pfizer’s MC4R antagonist PF-07258669.

Truce‐Smiles Rearrangement of Diaryliodonium Salts in Ionic Liquids

AbstractThe Truce‐Smiles rearrangement is an intramolecular SNAr reaction, enabling the formation of a new arene carbon‐carbon bond with sufficiently strong carbon‐centered nucleophile. Reported here are ortho‐tosylmethylene functionalized diaryliodonium salts, which can undergo an unprecedented Truce‐Smiles rearrangement in ionic liquids, resulting in sulfonyl‐substituted ortho‐iodo diarylmethanes as a powerful class of building blocks in chemical synthesis. The protocol features aryliodo moiety as a hyper nucleofuge, facilitating the formation of Meisenheimer complex within the migratory system.

2-(3-Bromophenyl)imidazo[2,1-b]oxazole

The microwave-assisted reaction of 2-nitroimidazole with 3-bromophenacyl bromide in the presence of potassium carbonate as a base and dimethylformamide as a solvent afforded 2-(3-bromophenyl)imidazo[2,1-b]oxazole. The formation of this compound was explained via a domino mechanism comprising an initial N-alkylation reaction of the imidazole substrate, followed by the base-promoted deprotonation of the position adjacent to the carbonyl to give an enolate anion that finally cyclizes via an intramolecular SNAr reaction, with the loss of the nitro group as potassium nitrite. Then, the proposed 1-(3-bromophenacyl)-2-nitroimidazole intermediate could be isolated by reducing the reaction time and was shown to be a precursor of the imidazo[2,1-b]oxazole final product.

Base-promoted tandem synthesis of 2-azaaryl indoline.

A novel tandem method to synthesize 2-azaaryl indoline promoted by LiN(SiMe3)2 from 2-azaaryl methyl amine and 2-fluoro benzyl bromides was developed. Mechanistic investigation indicated that this tandem cyclization was initiated by selective benzyl C-SN2 substitution followed by an intramolecular SNAr reaction. Diverse 2-azaaryl indoles could also be obtained via simple functional transformations.

Effective synthesis of regular ladder-type oligo(p-phenol)s via intramolecular SNAr O-arylation reaction

A series of novel ladder-type O-heteroarenes containing benzofuran units were effectively synthesized from the precursors via intramolecular SNAr reaction between F and OH groups in the backbone. The key intramolecular SNAr reaction was catalyst-free and highly efficient, moreover, the accurate annulation of fluorine atom ensured the regularity of the structure. We could smoothly obtain the ladder-type oligomer with seven oxygen bridges. The successes of the ladder-type oligomers also demonstrated the feasibility for preparing other regular oligomers and polymers with oxygen bridges.

NHC-Catalyzed Intramolecular SNAr Reaction of Styrenes for the Synthesis of Polyaromatic Compounds

NHC-Catalyzed Intramolecular SNAr Reaction of Styrenes for the Synthesis of Polyaromatic Compounds

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles.

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular SNAr or SN2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.

Copper-catalyzed construction of (Z)-benzo[cd]indoles: stereoselective intramolecular trans-addition and SN-Ar reaction.

Substituted benzo[cd]indoles are one of the most attractive frameworks because of their wide range of biological and optical activities. Herein, a copper-catalyzed one-step synthesis of biologically important polysubstituted benzo[cd]indoles starting from 8-alkynyl-1-naphthylamine derivatives is reported. In this protocol, many substituents tolerated the reaction conditions and produced (Z)-benzo[cd]indoles in good yields. Preliminary mechanistic studies indicated that the reaction proceeds via a stereoselective intramolecular trans-addition and SN-Ar reaction with high selectivity and high yields. The synthesized polysubstituted (Z)-benzo[cd]indoles possess sulfonamide building blocks, which make them candidates for bioactive molecules.

Construction of 5H‐Dibenzo[c,e]azepine Framework from Dibenzothiophene Dioxides andN‐Benzylimines through SNAr Reactions

AbstractTreatment of a mixture of dibenzothiophene dioxides and benzaldehydeN‐benzylimines with potassium hexamethyldisilazide induces sequential intermolecular and intramolecular SNAr reactions to eventually form the corresponding 5H‐dibenzo[c,e]azepines without any formation of the conceivable five‐membered fluorene derivatives.

Cyclizations and fragmentations in the alkylation of 6-chloro-5-hydroxy-4-aminopyrimidines with aminoalkyl chlorides.

Substituted aminopyrimidines are an important class of compounds, in part because they frequently show biological activity. Facile synthesis of polysubstituted aminopyrimidines is highly desirable for the synthesis of screening libraries. We describe a route to 4,6‐diamino‐5‐alkoxypyrimidines via a SNAr‐alkylation‐SNAr sequence from readily available 4,6‐dichloro‐5‐methoxypyrimidine, which allows the synthesis of such compounds with regiochemical control. The extension of this approach to alkylating agents bearing amino substituents led to unexpected and, in some cases, unprecedented products resulting from intramolecular SNAr cyclization and subsequent fragmentation.

Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C-N bonds.

Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by intramolecular nucleophilic aromatic substitution of metallated nitriles tethered by a urea linkage to a series of electronically unactivated heterocyclic precursors. The substitution reaction constitutes a ring expansion, enabled by the conformationally constrained tether between the nitrile and the heterocycle. Attack of the metallated urea leaving group on the nitrile generates a hydantoin that bridges the polycyclic products. X-ray crystallography reveals ring-dependant strain within the hydantoin.

SNAr Reaction Toward the Synthesis of Fluorinated Quinolino[2,3,4‐at]porphyrins

AbstractAn intramolecular SNAr displacement of one o‐fluorine atom of a meso‐pentafluorophenyl‐substituted porphyrin metal complex by a neighboring β‐amino functionality generated the corresponding meso‐fluorophenyl‐substituted metallo‐quinolino[2,3,4‐at]porphyrins that are not accessible using established quinoline‐annulation methodologies. The Cu(II), Ni(II), and Zn(II) complexes were thus prepared. The parent free base quinolino[2,3,4‐at]porphyrin is accessible only by demetallation of the copper or zinc complexes. A strong through‐space NMR‐spectroscopic coupling between the remaining o‐fluorine atoms on the annulated meso‐aryl group and the β‐hydrogen atom on the adjacent pyrrole moiety provide a clear spectroscopic signature for the annulation. Quinoline‐annulation alters the optical properties significantly. On account of the presence of the β‐amino functionality, all quinoline‐annulated porphyrins show strong halochromic responses with Brønsted acids and bases, the prerequisite for their potential use in chemosensing applications.

Oxygen‐ and Nitrogen‐Embedded Zigzag Hydrocarbon Belts

AbstractDespite the aesthetically appealing structures and tantalizing physical and chemical properties, zigzag hydrocarbon belts and their heteroatom‐embedded analogues remain challenging synthetic targets. We report herein the synthesis of diverse O/N‐doped zigzag hydrocarbon belts based on selective bridging of the fjords of resorcin[4]arene derivatives through intramolecular SNAr and palladium‐catalyzed intermolecular C−N bond formation reactions. Preorganized conformations of mono‐macrocyclic, half‐belt and quasi‐belt compounds were revealed to facilitate cyclization reactions to construct heteroatom‐linked octahydrobelt[8]arenes. The acquired products had strained square‐prism‐shaped belt structures in which all six‐membered heterocyclic rings adopted an unusual boat conformation with equatorially configured alkyl groups. The unprecedented heteroatom‐bearing belts also exhibited different photophysical and redox properties to those of octahydrobelt[8]arene analogues.