SNAr

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. 

Intermolecular displacements of a nitro group from p-dinitrobenzene proceed very rapidly to give various substitution products. o-Dinitrobenzene is as reactive as p-dinitrobenzene, but m-dinitrobenzene is less reactive. 

The anions derived from nitroalkanes, ketones, esters, and nitriles react with p-dinitroben-zene to give the corresponding products, as shown in Eq. 9.12 and Eq. 9.2.3 

SNAr reactions also provide an important strategy for the preparation of various kinds of diaryl ethers. p-Dinitrobenzene reacts with even sterically hindered phenols to give the corre- 

The reaction of p-cyanophenol with o-dinitrobenzene in the presence of KF in DMSO gives the corresponding diaryl ether in 95% yield (Eq. 9.4).7 

---

Compared with the aromatic electrophilic substitution approach, the SNAr approach general requires higher reaction temperatures. The polymers generally have well-defined structures. Therefore, it is more facile to control the structures of die products. In addition, it is more tolerable to some reactive functional groups, which makes it possible to synthesize reactive-group end-capped prepolymers and functional copolymers using functional monomers. 

Smith, Jason A., 431 Sn2+ compounds, 233 Sn4+ compounds, 232 SNAr reaction. See also Nucleophilic aromatic substitution reaction poly(arylene ether sulfone) synthesis via, 336-340... 

In 2005 we reported the synthesis of some sildenafil (3) analogues and their tyrosinase inhibitory potential [43]. The compoimds were synthesized using microwave irradiation in key steps, such as the SNAr reaction on important precursor bromopyrazole [44]. Their molecular structures are shown in Fig. 3. 

A short and practical synthesis of glucokinase activator 1 was developed utilizing a convergent strategy involving an SNAr coupling of the activated aryl fluoride 11 with hydroxypyridine 9. 

Parrot I, Wermuth C-G, Hibert M. Resin-bound thiophenols as SNAR-labile linkers Application to the solid phase synthesis of aminopyridazines. Tetrahedron Lett 1999 40 7975-7978. 

Table 10 includes the results for skin irritation. No clear results have been obtained. All models are in agreement only for the absence of irritative potential of BDE 100. Multiple results from ToxTree are due to the five different alerts used by the model (Schiff base formation, SNAr, Acyl transfer agent, skin sensitization, and Michael acceptor). A global evaluation of ToxTree data could suggest that all the analyzed compounds are not able to induce skin sensitization. These predictions are in clear contrast with that obtained by applying CAESAR and in partial agreement with the results of Toxsuite. 

SNAr substitutions of activated aromatic halides, especially aromatic fluorides, provide useful means for the construction of aromatic diethers or amines. Primary and secondary amines react with l, 2-dihalo-4,5-dinitrobenzene to give nitro group substitution at room temperature. The halogen substituents on the ring remain unsubstituted and can be used in further transformation (Eq. 9.5).8... 

Sawyer and coworkers have developed an efficient alternative Ullmann synthesis of diaryl ethers, diaryl thioethers, and diarylamines using the SNAr reaction. Phenol, thiophenol, or aniline reacts with an appropriate aryl halide, in the presence of KF-alumina and 18-crown-6 in acetonitrile or DMSO to give the corresponding diaryl ether or diaryl thioether as shown in Eqs. 9.6 and 9.7.9a... 

Zhu and coworkers have developed SNAr-based macrocyclization via biaryl ether formation.4 The first example of SNAr-based macrocyclization for synthesis of model carboxylate-binding pocket C-O-D rings of vancomycin was reported in 1994 (Scheme 9.3).10... 

To study generality of SNAr-based macrocyclization, effects of leaving groups and bases have been examined in synthesis of 14-membered macrocycles (Eq. 9.8).11 Evidently, fluorides... 

Double intramolecular SNAr reaction leads to a model bicyclic C-O-D-O-E ring, as shown in Eq. 9.9.12 Synthesis of a model 22-membered AB-C-O-D ring of vancomycin using similar strategy has been reported.13 Total synthesis of vancomycin has been accomplished by Nicolaou and coworkers.14... 

The SNAr reaction followed by intramolecular cyclization provides a useful method for the preparation of heterocyclic compounds, as summarized in Ref. 1. Reaction of 1-fluoronitroben-zene or 1,2-dinitrobenzene with guanidine in hot THF followed by treatment with t-BuOK gives 3-amino-1,2,4-benzotriazene 1-oxide in good yield (Eq. 9.11).19... 

Bonjoch and coworkers have developed a general synthetic entry to strychnos alkaloids of the curan type via a common 3a-(2-nitrophenyl)hexahydroindole-4-one intermediate. Total synthesis of (-)-strychnine is presented in Scheme 9.5.20 The first step is based on the SNAr reaction of o-iodonitrobenzene with 1,3-cyclohexanone. 

Biologically important arylamines, various kinds of heterocycles, and macrocyclic compounds have been prepared by using resin-bound nitro halo compounds via SNAr reactions. Such a process is very important for combinatorial synthesis of biologically important compounds. Typical examples are presented in Eqs. 9.13—9.21,22-31... 

Fullerene is nitrated with N204 to give hexanitro[60]fiillerene C60(NO2)4, which undergoes SNAr reaction with various nucleophiles.32... 

Carbanions of a-chloroalkyl phenyl sulfones react with nitrobenzenes to effect direct nucleophilic replacement of hydrogens located ortho and para to the nitro group (Eq. 9.24).38 A very important feature is that VNS of hydrogen usually proceeds faster than conventional SNAr of halogen located in equally activated positions (Eq. 9.25).38 The rule that VNS of... 

The Sundberg indole synthesis using aromatic azides as precursors of nitrenes has been used in synthesis of various indoles. Some kinds of aryl azides are readily prepared by SNAr reaction of aromatic nitro compounds with an azide ion. For example, 2,4,6-trinitrotoluene (TNT) can be converted into 2-aryl-4,6-dinitroindole, as shown in Eq. 10.60.83... 

Kraus has reported the synthesis of a tricyclic indole related to the pyrroloiminoquinone marine natural products (Scheme 10.9), in which an intramolecular SNAr and the reductive cyclization of a nitro aldehyde are involved as key steps.94 Related target compounds have been prepared by Joule and coworkers via a similar strategy.95... 

Rawal and Kozmin have utilized a Reissert type reaction in the total synthesis of tabersonine. The requisite nitro ketone is prepared by SNAr reaction of o-nitrophenylphenyliodonium fluoride with ketone silyl enol ether (Scheme 10.10).96... 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

An alternative method of six-membered ring formation has been reported utilizing an SNAr mechanism (Equation 31) <2002J(P1)790>. Chlorine is set up to leave by the electron-withdrawing influence of a group 138. The... 

---