Intramolecular Nucleophilic Aromatic Substitution Research Articles

A Photoinduced Annulation Strategy Towards a Novel Polycyclic Heteroaromatic Chromophore: Scope, Mechanism, Properties and Applications.

This article reports a detailed mechanistic and kinetic study of an unusual photoreaction leading to the (diazonia)tetrabenzonaphthacene skeleton. The photo‐triggered double intramolecular nucleophilic aromatic substitution (SNAr∗) has been investigated by varying the leaving groups. Photoreaction quantum yields have been determined and mechanistic insights have been supported by theoretical calculations using DFT and TD‐DFT methods. Additionally, we show that this light‐triggered formed diazonia constitutes a potent photosentitizer with a singlet oxygen generation quantum yield of 55 %, both in organic solvents and in water, which is an extremely relevant value in view of PDT applications or use as an oxidation photocatalyst in aqueous media. Once again, the experimental observations were supported by TD‐DFT calculations showing a large density of triplet states below the S1 excited state along with large spin‐orbit couplings. The reaction is not restricted to solutions but can also occur in solid PDMS matrices thus allowing for photochemical encoding of information that will progressively vanish upon prolonged UV‐exposure.

Transition-Metal-Free Synthesis of 2-Substituted Benzo[cd]Indoles via the Reaction of 1-Halo-8-lithionaphthalenes with Nitriles.

A simple and effective organolithium approach to the synthesis of 2-substituted benzo[cd]indoles from peri-dihalonaphthalenes and nitriles has been developed. The reaction proceeds via a surprisingly easy intramolecular aromatic nucleophilic substitution facilitated by the "clothespin effect". The discovered transformation provides good isolated yields, allows usage of an extensive range of nitriles, and demonstrates a good substituents tolerance. UV-absorption and NMR spectra of the obtained benzo[cd]indoles and their protonated forms demonstrated exclusive protonation to the indole nitrogen atom even in the presence of two NMe2 groups in positions 5 and 6 (i. e. "proton sponge" moiety).

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.

Highly Strained Oxygen‐Doped Chiral Molecular Belts of the Zigzag‐Type with Strong Circularly Polarized Luminescence

AbstractHerein we report a two‐directional cyclization strategy for the synthesis of highly strained depth‐expanded oxygen‐doped chiral molecular belts of the zigzag‐type. From the easily accessible resorcin[4]arenes, an unprecedented cyclization cascade generating fused 2,3‐dihydro‐1H‐phenalenes has been developed to access expanded molecular belts. Stitching up the fjords through intramolecular nucleophilic aromatic substitution and ring‐closing olefin metathesis reactions furnished a highly strained O‐doped C2‐symmetric belt. The enantiomers of the acquired compounds exhibited excellent chiroptical properties. The calculated parallelly aligned electric (μ) and magnetic (m) transition dipole moments are translated to the high dissymmetry factor (|glum| up to 0.022). This study provides not only an appealing and useful strategy for the synthesis of strained molecular belts but also a new paradigm for the fabrication of belt‐derived chiroptical materials with high CPL activities.

Highly Strained Oxygen-Doped Chiral Molecular Belts of the Zigzag-Type with Strong Circularly Polarized Luminescence.

Herein we report a two-directional cyclization strategy for the synthesis of highly strained depth-expanded oxygen-doped chiral molecular belts of the zigzag-type. From the easily accessible resorcin[4]arenes, an unprecedented cyclization cascade generating fused 2,3-dihydro-1H-phenalenes has been developed to access expanded molecular belts. Stitching up the fjords through intramolecular nucleophilic aromatic substitution and ring-closing olefin metathesis reactions furnished a highly strained O-doped C2 -symmetric belt. The enantiomers of the acquired compounds exhibited excellent chiroptical properties. The calculated parallelly aligned electric (μ) and magnetic (m) transition dipole moments are translated to the high dissymmetry factor (|glum | up to 0.022). This study provides not only an appealing and useful strategy for the synthesis of strained molecular belts but also a new paradigm for the fabrication of belt-derived chiroptical materials with high CPL activities.

Enantioselective Intramolecular α‐Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

AbstractA practical, transition metal‐free method allows the enantioselective synthesis of α,α‐diarylmethylamines by asymmetric α‐arylation of benzylamines. Enantioselective lithiation of N′‐aryl‐N‐benzyl‐N‐isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α‐diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an “azatropic shift” with retention of configuration, the product of which may be hydrolysed to the target amine.

Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine.

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N'-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an "azatropic shift" with retention of configuration, the product of which may be hydrolysed to the target amine.

Base-Promoted Decarboxylative Annulation of Methyl 2-(2-Bromophenyl)acetates and Ynones to Access Benzoxepines

A simple and efficient base-mediated decarboxylative annulation of ynones with methyl 2-(2-bromophenyl)acetates has been developed. A broad range of benzoxepines were prepared with a broad substrate scope and high regioselectivity in moderate to excellent yields under transition-metal-free conditions. This method proceeds through a tandem [2 + 4] annulation, ring-opening decarboxylative reaction, and the intramolecular nucleophilic aromatic substitution reaction. Additionally, the key intermediates were successfully obtained and characterized unambiguously by single-crystal X-ray crystallography, which could favorably support a decarboxylative annulation mechanism. Furthermore, gram-scale reaction and synthetic applications for the further functionalization are also studied.

Synthesis of Benzofuropyridines and Dibenzofurans by a Metalation/Negishi Cross-Coupling/SNAr Reaction Sequence.

An efficient methodology for the synthesis of benzofuropyridines and dibenzofurans from fluoropyridines or fluoroarenes and 2-bromophenyl acetates is reported. This streamlined one-pot procedure consists of a four-step directed ortho-lithiation, zincation, Negishi cross-coupling, and intramolecular nucleophilic aromatic substitution, allowing for the facile assembly of a diverse set of fused benzofuro heterocycles.

A Critical Review on Recent Advances in Base-Assisted Smiles Rearrangement

Abstract: Rearrangement reactions of organic substrates is a versatile and sustainable tool in the construction of complex and bioactive organics by virtue of their atom-economic, stepeconomic and waste-, time- as well as energy-minimizing attributes. The X → C (or Y) aryl rearrangement reaction through an intramolecular nucleophilic aromatic substitution is referred to as Smiles rearrangement. The Smiles rearrangement enables access to complex natural products and is a useful tool to obtain various types of compounds with diversified applications, which have undergone a potent revival in recent years. In this review, we summarize the recent reports on Smiles rearrangement and most of them require a base. A few examples of the reported base-free Smiles rearrangements were also reviewed to provide comprehensive information on the selected topic. The literature review covers the published work on Smiles rearrangement reaction since 2017. The published work in these articles include simple Smiles, Truce-Smiles, radical Smiles, Ugi-Smiles, light-assisted Smiles, Dohmori-Smiles, electrochemical Smiles and phospha-Smiles rearrangement reactions for the construction of a variety of organic compounds including acyclic, heterocyclic, carbocyclic and polycyclic compounds. The formation of organic compounds with unusual ring sizes has also been discussed in the published work. Several domono/sequential reactions were also observed in these reports involving Smiles rearrangement as a crucial step. The selected examples demonstrate the synthetic power of this approach and hence this review may be highly useful to the synthetic chemists aimed to use Smiles rearrangement in their plan.

Synthesis of α‐ and β‐Carbolines by a Metalation/Negishi Cross‐Coupling/SNAr Reaction Sequence

AbstractA methodology for the synthesis of α‐ and β‐carbolines from fluoropyridines and 2‐haloanilines is reported. This procedure consists of a four‐step directed ortho‐lithiation, zincation, Negishi cross‐coupling, and intramolecular nucleophilic aromatic substitution, providing access to a diverse set of functionalized carbolines. While the procedure is applicable to batch conditions, the generation of arylzinc intermediates in continuous flow has been demonstrated.magnified image

Non-Stabilized Vinyl Anion Equivalents from Styrenes by N-Heterocyclic Carbene Catalysis and Its Use in Catalytic Nucleophilic Aromatic Substitution.

A protocol for the catalytic nucleophilic activation of unactivated styrenes is reported, which enables the generation of a non-stabilized alkenyl anion equivalent as a transient intermediate. In the reaction, N-heterocyclic carbenes add across styrenes to generate ylide intermediates, which can then be used in intramolecular nucleophilic aromatic substitution reactions of aryl fluorides, chlorides, and methyl ethers. The method allows for straightforward access to complex polyaromatic compounds.

Construction of Benzosultam‐Containing Fused‐ and Linked‐Biheterocycles by a Cascade Double Nucleophilic Cyclization

AbstractAlthough nucleophilic aromatic substitution (SNAr) and many nucleophilic epoxide ring‐opening reactions proceed under similar anionic conditions, the literature examples of using these reactions in tandem for the construction of heterocyclic compounds are scarce. In this article, we disclose a detailed account of the synthesis of benzothiaoxazepine‐1,1‐dioxide‐containing fused‐ and linked‐biheterocycles by a base‐mediated, exo‐selective intramolecular epoxide‐opening/intramolecular nucleophilic aromatic substitution cascade of epoxide‐tethered ortho‐fluorobenzenesulfonamides. A wide range of substrates exhibited high overall yields and complete regio‐ and diastereoselectivity

Nitrile Synthesis via Desulfonylative-Smiles Rearrangement.

Herein, we designed a simple nitrile synthesis from N-[(2-nitrophenyl)sulfonyl]benzamides via base-promoted intramolecular nucleophilic aromatic substitution. The process features redox-neutral conditions as well as no requirement of toxic cyanide species and transition metals. Our process shows broad scope and various functional group compatibility, affording a variety of (hetero)aromatic nitriles in good to excellent yields.

Fluorosulfonylferrocene, (Trifluoromethylsulfonyl)ferrocene and New Ferrocenyl Sulfonates: Directed ortho Lithiation and New Anionic Thia‐Fries Rearrangements at Ferrocene

AbstractFerrocenyl triflates are known to undergo anionic thia‐Fries rearrangements at low temperature in high yields. In order to expand the scope of this reaction, ferrocenyl sulfonates and sulfonylferrocenes were prepared and their reactivity investigated. Treatment of ferrocenyl fluorosulfonate with lithium 2,2,6,6‐tetramethylpiperidide gave rise to a new anionic thia‐Fries rearrangement at ferrocene. The formation of a rare oxathiine was observed with ferrocenyl (pentafluorophenyl)sulfonate as a result of an ortho lithiation and a subsequent intramolecular nucleophilic aromatic substitution. In contrast to fluorinated ferrocenyl sulfonates, fluorosulfonylferrocene as well as (trifluoromethylsulfonyl)ferrocene underwent ortho lithiation under comparable reaction conditions.

Triarylmethanes and their Medium-Ring Analogues by Unactivated Truce-Smiles Rearrangement of Benzanilides.

Intramolecular nucleophilic aromatic substitution (Truce–Smiles rearrangement) of the anions of 2‐benzyl benzanilides leads to triarylmethanes in an operationally simple manner. The reaction succeeds even without electronic activation of the ring that plays the role of electrophile in the SNAr reaction, being accelerated instead by the preferred conformation imposed by the tertiary amide tether. The amide substituent of the product may be removed or transformed into alternative functional groups. A ring‐expanding variant (n to n+4) of the reaction provided a route to doubly benzo‐fused medium ring lactams of 10 or 11 members. Hammett analysis returned a ρ value consistent with the operation of a partially concerted reaction mechanism.

Base-mediated synthesis of benzimidazole-fused 1,4-benzoxazepines via sequential intermolecular epoxide ring-opening/intramolecular SNAr reactions

We have developed a transition-metal-free, practical route to benzimidazole-fused 1,4-benzoxazepines. Operationally, the protocol involves a K2CO3-mediated intermolecular ring opening of terminal epoxides by 2-(2-fluorophenyl)benzimidazole, followed by an intramolecular nucleophilic aromatic substitution (SNAr) reaction of the resulting products in the presence of NaH. We have also achieved an 11-step synthesis of a chroman-linked benzimidazole-fused 1,4-benzoxazepine using a phenoxide-ion induced 6-exo intramolecular epoxide ring-opening and an alkoxide-ion induced intramolecular SNAr reaction as key steps.

Synthesis of a conjugated polymer with ring-fused pyridinium units via a postpolymerization intramolecular cyclization reaction

The synthesis of a novel conjugated polymer containing fused pyridinium units in its main chain is reported. A precursor polymer possessing pyridine and tetrafluorophenylene moieties was reacted in the presence of Lewis acid additives to promote the intramolecular nucleophilic aromatic substitution (SNAr) reaction. The polymer reaction with BE3-OEt2 gave a product polymer soluble in polar organic solvents, and the successful formation of fused pyridinium ring structures was spectroscopically confirmed. The electrochemical and optical properties of the synthesized polymers were also investigated, suggesting that the polymer product has a narrower band gap than the precursor polymer. The synthesis of a novel conjugated polymer containing fused pyridinium units in its main chain is reported. A precursor polymer possessing pyridine and tetrafluorophenylene moieties was reacted in the presence of Lewis acid additives to promote the intramolecular nucleophilic aromatic substitution (SNAr) reaction. The polymer reaction with BE3-OEt2 gave a product polymer soluble in polar organic solvents, and the successful formation of fused pyridinium ring structures was spectroscopically confirmed. The electrochemical and optical properties of the synthesized polymers were also investigated.

Aspects of Phosphaallene Chemistry: Heat-Induced Formation of 1,2-Dihydrophosphetes by Intramolecular Nucleophilic Aromatic Substitution and Photochemical Generation of Tricyclic Phosphiranes.

3H-Phosphaallenes are accessible on a new and facile route and show a fascinating chemical behavior. The thermally induced rearrangement of Mes*P═C═C(H)R' (R' = tBu, Ad) afforded by C-H activation, isobutene elimination, and C-C and P-H bond formation bicyclic 1-benzo-dihydrophosphetes (2) with PC3 heterocycles. DFT calculations suggest a mechanism with intramolecular nucleophilic aromatic substitution and replacement of an alkyl group by the nucleophilic α-C atom of the phosphaallene. These bicycles formed W(CO)5 complexes (3) or afforded 1,2-dihydrophosphetes with P-bound alkenyl groups by catalyst-free hydrophosphination of alkynes (4 and 5). The resulting bulky phosphines formed complexes with IrCp*Cl2, RuCl2, AuCl, or CuO3SCF3. The Ru atom is coordinated by the P atom and a phenyl group. Irradiation of TripP═C═C(H)tBu led by the insertion of the central C atom of the P═C═C group into the α-C-H bond of an iPr substituent and by C-C and P-C bond formation to a new isomer of phosphaallenes, 10, which features a strained PC2 heterocycle. It formed adducts with M(CO)5 (M = Cr, Mo, W) and AuCl and reacted with SO2Cl2 by cleavage of one of the phosphirane P-C bonds to yield PC4 or PC5 heterocycles. Hydrolysis yielded a PC5 compound with a P(O)Cl group.

Rhodium-catalyzed coupling of arenes and fluorinated α-diazo diketones: synthesis of chromones.

Rhodium(iii)-catalyzed C-C coupling of heteroarenes and fluorinated α-diazo diketones has been realized for the facile synthesis of 3-arylchromones. The reaction proceeds via chelation-assisted C-H activation, carbene insertion, and uncatalyzed intramolecular nucleophilic aromatic substitution, with C-F cleavage being accommodated in the nucleophilic aromatic substitution step. Three classes of heteroarenes have been defined with decent functional group tolerance.