Intramolecular Reactions Nucleophilic Aromatic Substitution

1 Heteroatom Heteroatom Aromatic Rearrangements (Smiles Rearrangement) The 

In studies toward the synthesis of glycyrol, Kim and coworkers employed a novel precursor, iodium acetate salt 7, which was successfully incorporated into a novel Smiles rearrangement, ultimately leading to the first total synthesis of glycyrol (Figme 18.1) [4]. 

A more recent example sees the conversion of an aryl ether (9) to an Af-aryl-2-hydroxypropion-amide (10) in high overall yields from the starting materials, ultimately leading to a two-step Smiles-Sonogashira synthesis of indoles from 2,3-dihalophenols [5]. 

The Smiles rearrangement is also widely used on heterocyclic systems however, due to the nature of this review, these will not be discussed here. 

2 Heteroatom Carbon Aromatic Rearrangements (Truce-Smiles Rearrangement) 

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The reaction of 3-halo-4-aminopyridines with acyl chlorides in the presence of triethy-lamine gives pyridin-4-yl a-substituted acetamides in which an Al-acylated intermediate reacts intramolecularly via nucleophilic aromatic substitution resulting in a formal two-carbon insertion (Scheme 205). " ... 

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-... 

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 ... 

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. 

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. ... 

A convenient synthesis of 2-mercaptobenzothiazoles 44 features an exclusive ortho-selective nucleophilic aromatic substitution reaction of or//zo-haloanilines 41 and subsequent intramolecular cyclization of the intermediate O-ethyl carbonodithioates 43 <05JHC727>. 2-Mercaptobenzothiazoles 44 are readily converted to the corresponding 2-chlorobenzothiazoles 45 upon treatment with sulfuryl chloride. 

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 condensation reactions of activated thiol compounds (e.g., a-thioglycolate derivatives) have been utilized to prepare fused thiophene compounds. For example, treatment of imine 5 with methyl thioglycolate gave the nucleophilic aromatic substitution... 

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. 

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