Intramolecular nucleophilic aromatic

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

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). 

Different nucleophiles such as methanol, allylsilanes, silyl enol ethers, trimethylsilyl-cyanide, and arenes can be used in this process [62]. When the sulfide itself contains an unsaturated or aromatic fragment and the process is carried out in the absence of a nucleophile, an intramolecular anodic sub-stitution/cyclization might occur [61-63]. Methyl esters of 2-benzothiazolyl-2-alkyl or aryl-acetic acid, oxidized in MeOH/Et4 NCIO4 or H2SO4 in the presence of CUCI2, form 2,2-dimethoxy products (Eq. 7) [64]. 

A classical application of cyclopropane rings in "reactivity inversion", in which a previously negatively polarised y-carbon atom (see 29) to a carbonyl group is inverted by formation of a cyclopropane ring (30) and is then intramolecularly attacked by a nucleophilic aromatic ring, is found in the synthesis of hydrophenanthrene system 11 (Scheme 5.19) developed by Stork in 1969 [21]. 

Intramolecular nucleophilic aromatic rearrangement. General scheme ... 

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) . 

Pyrrolobenzoxazepinones 2 are prepared from the l-(2-halobenzoyl)- or l-(2-methoxyben-zoyl)-2-pyn olidinemethanols 1 by formation of the alkoxide, followed by intramolecular nucleophilic aromatic substitution3,25,26,28,32. 

Nucleophilic aromatic substitutions involving loss of hydrogen are known. The reaction usually occurs with oxidation of the intermediate either intramolecularly or by an added oxidizing agent such as air or iodine. A noteworthy example is the formation of 6-methoxy-2-nitrobenzonitrile from reaction of 1,3-dinitrobenzene with a methanol solution of potassium cyanide. In this reaction it appears that the nitro compound itself functions as the oxidizing agent (10). 

Cycloamidation has been used extensively to prepare 17-membered cycloisodityrosines. The acyclic biaryl ether precursors were prepared by methods including the Ullmann reaction 2-5 and nucleophilic aromatic substitution (SNAr)J6 7 Since these methods have all been used intramolecularly in cyclization reactions, they will be discussed in Sections 9.5.3 and 9.5.4. Evans and co-workers employed the pentafluorophenyl ester method of macrolactamization 8] to prepare 11, an intermediate in their total synthesis of OF4949-III (7) (Scheme 2)J3 In this case, the acidic removal of a Boc group was employed to release the cyclization substrate, although hydrogenolysis of a Z group is also effective 3 ... 

Breternitz, H.-J. Schaumann, E. Adiwidjaja, G. Cyclization of deprotonated 2-phenyl-l-tosylaziridine. A surprising example of an intramolecular nucleophilic aromatic addition. Tetrahedron Lett. 1991, 32, 1299-1302. 

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. 

The aromatic phenol was varied to explore the scope of the O-to-C conversion with mannosyl phosphates. Using phosphate 9, the a-C-mannosides of 2-naphthol and 3-benzyloxy phenol (23 and 25, Table 1) were synthesized in excellent yield. O-Mannosides were obtained exclusively with less nucleophilic aromatic systems, such as 3-acetoxy phenol. Several non-phenolic aromatic systems were unsuccessful in the formation of C-aryl or O-aryl glycosides. Reaction of 9 with furan, thiophene, trimethoxybenzene, and indole in the presence of TMSOTf did not result in any product formation. Interestingly, activation of 9 in the absence of any aromatic nucleophiles gave 26 as the major product via an intramolecular C-glycosylation (Figure 1) (79). 

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. 

Intramolecular nucleophilic substitution reactions of chlorine " " or bromine with alco-holates lead to tetrahydropyrans. The alcoholate can be formed in situ by deprotccting an alcohol.Activated aromatic chlorides give in nucleophilic aromatic substitution reactions a six-membered heterocyclc, e.g, reaction of 1 to give 2. ... 

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