Intramolecular nucleophilic aromatic substitutions

Pyrazolo-[3,4i ]-quinolines and -pyrazoles have been synthesized by reacting [i-chlorovinylaldehydes and hydrazine or phenyl hydrazine using a catalytic amount of p-toluenesulfonic acid (PTSA) under the action of microwave irradiation. The yields are much better than under the action of A using the same conditions [105] (Eq. 55). 

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The group of Grieco has presented a method for efficiently performing macrocy-clizations on a solid phase (Scheme 7.31) [48]. The preparation of the macrocyclic peptides required several standard transformations, which are not described in detail herein. The final intramolecular nucleophilic aromatic substitution step was carried out under microwave irradiation at 50 °C in a dedicated CombiCHEM system (see Fig. 3.9) utilizing microtiter plates in a multimode batch reactor. The cycli-zation product was obtained in good yield after a reaction time of 10 min and sub-... 

Excited-state intramolecular nucleophilic aromatic substitutions are known as photo-Smiles rearrangements. Ealier, these were reported for 2,4-dinitrophenyl ethers and. v-lriazinyl ethers32. The exploratory33 and mechanistic34 studies on photo-Smiles rearrangements of p-(nitrophenoxy)- >-anilinoalkanes were carried out (equation 28). 

Furthermore, pyrazole 366 reacts with phthalazine (Scheme 132) to afford pyrazolo[3, 4 4,5]pyrido[6,l-a]phthalazine (367). From a mechanistic viewpoint, no 1,6-dipolar cyclization occurs. Instead, an intramolecular nucleophilic aromatic substitution to the heteroarene is likely. Isoquinoline leads to zwitterionic 368 (94JOC3985). 

Intramolecular nucleophilic aromatic substitution on 243 allowed l,4-dihydropyridazin-3(2//)-one ring construction (Equation 58) . Similarly, a tetrahydropyridazine unit could be constructed starting from 244 (Equation 59) . 

Parker, K. A. Coburn, C. A. Regioselectivity in intramolecular nucleophilic aromatic substitution. Synthesis of the potent anti HIV-18-halo TIBO analogues. J. Org. Chem. 1992, 57, 97— 100. 

Intramolecular nucleophilic aromatic substitution of a tricarbonyl chromium derivative in the presence of sodium hydride and dimethoxyethane gave 33 which on photolysis yielded bicyclo[3.2.0]hept-3-en-7-one derivative 462 with ee>98% (Scheme 16). The mechanistic pathways of the reaction have been discussed <2000TA1927, 2005TA971>. 

These results clearly show that the potential energy surface can contain a series of minima. The fact that selectivity in re-attack by the F ions can be observed indicates that the differences between the energy barriers for the secondary reactions control the distribution of the final products. The multistep character of these processes is further illustrated by the reactions observed when enolate anions are used as reactant ions. The ambident enolate anions may react with methyl pentafluorophenyl ether at the carbon or the oxygen site. If they react with the carbon site at the fluorine-bearing carbon atoms, then the molecule in the F ion/molecule complex formed contains relatively acidic hydrogen atoms so that proton transfer to the displaced F ion may occur. An example is given in (47) where the enolate anion, generated by HF loss, is not observed. An intramolecular nucleophilic aromatic substitution occurs instead and leads to a second F ion/ molecule complex. The F" ion in this complex then re-attacks the substituted benzofuran molecule formed, either by proton transfer or SN2 substitution. 

With respect to this, Ellman and coworkers [16], Zhu and coworkers [17], Amusch and Pieters [18], and Liskamp and coworkers [19] have prepared (monocyclic) mimics of the D-E part of the cavity of these antibiotics via an intramolecular nucleophilic aromatic substitution [16-18] or a Sonogashira-based macrocyclization [19] (Figure 1.4). Recently, a bicydic mimic of the C-D-E cavity, which was prepared by a Stille reaction followed by tandem ring-dosing metathesis (9, Figure 1.4), was described by liskamp and coworkers [20]. Considerable challenges lie ahead for the synthetic chemist in order to develop practical syntheses of mimics of vancomydn capable of binding not only D-Ala-D-Ala, but also cell wall parts of resistant bacteria, i.e. D-Ala-D-lactate. 

A similar intramolecular nucleophilic aromatic substitution has been used for the synthesis of pyrrolo[l,2-a] indoles in astonishing high yield from Z-enaminonitriles (equation 108)160. 

Mechanistically, the one-pot transformation can be rationalized by a sequence of chemoselective coupling of ort/to-halogenated (hetero)aromatic acid chlorides 81 and electron rich terminal alkynes 4, followed by nucleophilic addition of the sulfide ion to the a,p-unsaturated system 86 to furnish the anionic Michael adduct 87, and finally an intramolecular nucleophilic aromatic substitution in the sense of an addition-elimination process concludes the sequence (Scheme 46). 

Smiles rearrangement. Intramolecular nucleophilic aromatic substitution in alkaline solution resulting in the migration of an aromatic system from one heteroatom to another. 

Benzylsulfonamides (138) and aldehydes can be combined under strongly acidic conditions to afford 2,3-benzothiazine 2,2-dioxides (139) via a preparative scale intramolecular sulfonamido-methylation. This highly effective procedure provides a rapid entry into the 2,3-benzothiazine ring skeleton (Scheme 26). When this reaction is carried out with weak acids or short reaction times, uncyclized intermediates can be isolated <86JHC1701>. The treatment of 3-nitrobenzylamine derivatives (140) with NaOH in DMSO leads to 2,3-benzothiazines (141a) and (141b) by an intramolecular nucleophilic aromatic substitution (Scheme 26) <92S57i>. 

Intramolecular nucleophilic aromatic substitution of (106) was useful for a synthesis of dihydro-pyrrolizines (107) <85TL283i>. 

Pt(DuPhos)(Cl)(Ph)] produces the secondary phosphido complexes 87, which after alkylation by 84 and subsequent deprotonation form phosphido complexes 89. At this point, a proposed intramolecular nucleophilic aromatic substitution gives 90, bearing a coordinated phosphacycle. Displacement of the product by an incoming phosphine substrate and NaOTMS completes the catalytic cycle. 

Intramolecular nucleophilic aromatic substitution in alkaline solution resulting in the migration of an aromatic system from one heteroatom to another. The two-carbon unit joining X and Y is usually part of an aromatic ring but may also be aliphatic ... 

In an alternative synthesis, a two-step sequence involved an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution to provide rapid access to biaryl-ether-containing macrocycles in solution phase and solid phase (Figure 11.34). 55 Using isonitriles, aldehydes, amines, and carboxylic acids as inputs for the Ugi reaction, dipeptides 70 were formed. Upon cyclization of 70 with K2CO3 in DMF, macrocycles 71 with four points of diversity were obtained. Moreover, the presence of the nitro group allowed the introduction of further structural variation. In the solid-phase synthesis, the Ugi condensation used isonitriles attached to a Wang resin. 

The Smiles rearrangement occurs via an intramolecular nucleophilic aromatic substitution as shown below. ... 

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