Nucleophilic Aromatic Substitution

Crampton, Michael R.

doi:10.1002/9781118754887.ch6

Cited by 12 publications

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“…The synthesis of many antibiotics, chemotherapeutics, and herbicides via S N Ar has solidified this reaction class into many organic textbooks . However, S N Ar suffers from some limitations: (1) reactions generally require pairing strong nucleophiles with very electron-deficient fluoroarenes and (2) strongly polar aprotic solvents are needed to operate at low temperatures . These two criteria preclude weak nucleophiles such as acids or water from engaging in S N Ar with “electron-rich” fluoroarenes .…”

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Transition-Metal-Mediated Nucleophilic Aromatic Substitution with Acids

et al. 2016

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Index Page Experimental General Considerations S2 Synthesis of Q 2 FB (2) S2 Synthesis of (Q 2 FB)Rh(TFA)(COE) (3) S2-S3 Synthesis of (Q 2 FB)Rh(TFA) 3 (1) S3 General procedure for catalytic S N Ar in HTFA S3 NMR spectra Table of NMR chemical shifts S4 NMR spectra of 2 S5-S6 NMR spectra of 3 S6-S10 NMR spectra of 1 S10-S13 19 F NMR spectra of CF 3 C(O)F S13 19 F NMR spectra of CH 3 C(O)F S14 NMR spectra of intermediate 4 S14-S16 NMR spectra of proposed 5a and 5b S17-S18 NMR spectra of catalytic defluorination S19 Kinetics Defluorination of 1 S20-S21 References S22 DFT Calculations S23-S30 S2 Experimental General Considerations. Unless otherwise noted, all synthetic procedures were performed under anaerobic conditions in a nitrogen filled glovebox or by using standard Schlenk techniques. Glovebox purity was maintained by periodic nitrogen purges and was monitored by an oxygen analyzer (O 2 < 15 ppm for all reactions). Tetrahydrofuran, pentane and diethyl ether were dried by distillation from sodium/benzophenone. Benzene, hexanes, and methylene chloride were purified by passage through a column of activated alumina. Benzene-d 6 , chloroform-d 1 , and tetrahydrofuran-d 8 were stored over 4Å molecular sieves in a nitrogen atmosphere. 1 H NMR spectra were recorded on a Varian Mercury Plus 300 MHz or a Varian Inova 500 MHz spectrometer, and the 13 C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (operating frequency 126 MHz). All 1 H and 13 C NMR spectra are referenced against residual proton signals (1 H NMR) or the 13 C resonances of the deuterated solvent (13 C NMR). {(COE) 2 Rh(μ-TFA)} 2 was prepared according to published literature procedures. 2 All other reagents were used as purchased from commercial sources. Synthesis of 8,8'-(4,5-difluorobenzene)diquinoline (Q 2 FB) (2). Quinolin-8-ylboronic acid (1.50 g, 8.67 x10-3 mol, 2.4 equiv.), 1,2-dibromo-4,5-difluorobenzene (0.985 g, 3.62 x10-3 mol, 1 equiv.), Pd(PPh 3) 4 (0.418 g, 3.62 x10-4 mol, 0.10 equivalents), and K 3 PO 4 (17.0 g, 8.01 x10-2 mol, 22 equiv.) were combined into the 250 mL Schlenk flask. Under an inert atmosphere, degassed dimethylformaldehyde (60 mL) and degassed DI water (60 mL) were added to the Schlenk flask, and the flask was fitted with a glass stopper and sealed. The glass stopper was secured to the Schlenk flask with several rubber bands, and then the reaction mixture was heated in an oil bath at 110 °C with stirring for 14 h. Afterwards, the reaction mixture was allowed to cool to room temperature, during which the aqueous and organic layers separated. The lower aqueous phase was separated from the organic phase by separatory funnel and discarded. The organic layer was collected, and a copious amount of DI water (500 mL) was added to precipitate a yellow oily solid. The solid was collected by filtration and then dissolved in Et 2 O (30 mL) and filtered. The filtrate was collected and reduced under mild pressure to an oil. The product was purified by column chromatography (silica). The mono-coupled product was removed as ...

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Transition-Metal-Mediated Nucleophilic Aromatic Substitution with Acids

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“…Moreover, the presence of the nitro electron-withdrawing group in the ortho-position promotes aromatic nucleophilic substitution [6,7]. Subsequently, the second equivalent of base promotes the formation of the furan heterocycle by releasing a nitrite ion, known to be a relatively good leaving group [8,9]. Therefore, the nitro group plays a dual role in this synthesis, namely as activator in the first nucleophilic substitution and as the leaving group in the final step of furan cyclization.…”

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9-Methoxynaphtho[1,2-b]benzofuran

Miani

Vigna

Mancini

2023

Molbank

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A highly selective one-pot microwave-assisted synthesis of 9-methoxynaphtho[1,2-b]benzofuran was obtained by treating 1-naphthol with 1-bromo-4-methoxy-2-nitrobenzene and two molar equivalents of potassium tert-butoxide in dimethyl sulfoxide. The selectivity in the production of the title compound was addressed by the suitable position of the bromine and nitro group on the aryl reagent. Moreover, we highlight how the nitro group plays a dual role, as activator in the first nucleophilic substitution with the release of bromide ion and then as the leaving group in the furan cyclization. Eventually, the product was structurally characterized by MS and extensive NMR analyses.

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Alkylation of Nitroaromatics with Trialkylborane

Shifman

Palani

Hoz

2000

Angew. Chem. Int. Ed.

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Aromatic substitution is one of the most thoroughly studied reactions.[1] Yet in spite of the wealth of mechanistic knowledge and numerous synthetic applications, this paper reports a facile and hitherto unknown alkylation procedure for nitroaromatics.When p-dinitrobenzene (1) is treated with trialkylborane in the presence of potassium tert-butoxide in tert-butyl alcohol at room temperature for five minutes, it furnishes p-alkylnitrobenzene (2, Equation 1) in high yield. Equivalent amounts of the three componentsÐ1, trialkylborane, and baseÐwere found to be essential for the completion of the reaction. When the amount of trialkylborane or base is reduced below this ratio, the substrate is consumed in an amount equivalent to the reagent present in the minimum concentration. Since an excessive amount of base results in the formation of p-tertbutoxynitrobenzene, a small excess (approximately 10 %) of the borane reagent was usually employed. When the reaction was performed with triethylborane, by-products 3 ± 6 were isolated in addition to 70 % of 2 (R Et, Scheme 1). Scheme 1. By-products obtained in the reaction of p-dinitrobenzene with triethylborane.The reaction can also take place in THF. However, the yields are slightly lower with the major difference being the presence of approximately 15 % of p-tert-butoxynitrobenzene amongst the products. Using two equivalents of triethylborane increased the yield to 85 % and no p-tert-butoxynitrobenzene was formed. Temperature sensitivity was also observed. When the reaction was conducted at temperatures below 25 8C the rate decreased drastically. At 0 8C, for example, the reaction does not progress, to a significant extent, even after 2 hours.Using tributylborane, the yield of p-butylnitrobenzene was also in the range of 70 ± 80 % and no isomerization on the butyl chain was observed. However, the reaction failed with triphenylborane. Even after 24 hours no para phenylation was observed. When the substrate was changed to p-nitrobenzaldehyde and the previous reaction conditions were employed in THF, only 7 % of 2 (from departure of CHO) was observed after 12 hours.Aluminum, the homologue of borane, was found to be much less reactive. Treatment with triethylaluminum, under identical reaction conditions gave only 19 % (NMR yield) of p-ethylnitrobenzene after 12 h at room temperature although over 40 % of 1 was consumed.The reaction is unlikely to be a radical or a radical ± anionic chain mechanism of a type similar to the Srn1 reaction [2] since it also proceeds smoothly in 2-propanol, a solvent which rapidly reacts with free radicals. In addition, no inhibition of the reaction by 5 mol % galvinoxyl is observed and the reaction is not catalyzed by the laboratory light. On the other hand, p-dinitrobenzene is known to be a powerful electron acceptor [3] and trialkylboranes are known to yield very rapidly, with a rate constant of 10 8 m À1 s À1, alkyl radicals when reacted with oxy-radicals.[4] Based on the nature of the reactants and the aforementioned results a tentative noncha...

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Nucleophilic Aromatic Substitution

Cited by 12 publications

References 224 publications

Transition-Metal-Mediated Nucleophilic Aromatic Substitution with Acids

Transition-Metal-Mediated Nucleophilic Aromatic Substitution with Acids

9-Methoxynaphtho[1,2-b]benzofuran

Alkylation of Nitroaromatics with Trialkylborane

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