SNAr reactions

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. 

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. 

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-... 

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... 

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... 

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... 

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 expeditious microwave assisted SNAr reaction with cyclic amines has been reported for activated aromatic substrates [83] (Eq. 29). 

Solvent-free SNAr reactions under solid-liquid PTC conditions were realized by using methoxide or phenoxide as nucleophiles. The main results, and comparison with those from classical heating, are indicated in Tab. 5.24 for activated (e.g. 4-nitro-halobenzenes) or nonactivated (e.g. a-naphthyl halides) substrates [74]. 

Sn2 and SNAr Reactions In these reactions the metal atom attacks aliphatic or aromatic carbon bonded to X, respectively. A stronger nucleophilic metal as well as a better leaving group X (I>Br>Cl>F) facilitates, whereas steric hindrance in R slows these types of oxidative addition [193, 194]. SNAr reactions are favored by electron-withdrawing substituents Y in the case of the substrates 4-YQH4X [2], Sn2 [27, 29, 89, 117, 180, 181] and SNAr [31, 33, 62-67, 95, 100, 107-109] mechanisms have been suggested frequently for zerovalent d10 complexes such as [L M] (M = Ni, Pd, Pt L=tertiary phosphine =2,3,4). For example ... 

Iodopyrimidine 7 was prepared by iodination of 2,4-diaminopyrimidine 6, which was derived from commercially available 2-amino-4-chloro-6-methylpyrimidine (5) via an SNAr reaction with ammonia [8]. Similarly, iodination of 6-chloro-2,4-dimethoxypyrimidine (8) with N-iodosuccinimide in trifluoroacetic acid led to dihalopyrimidine 9 [9],... 

A very interesting (and important) detail of the SnAr reaction showing positive catalysis is the dependence of catalysed and uncatalysed processes on the temperature and was investigated in several instances270-274. There are systems271,272 in which the experimental reaction rate constant (in s 1 mol-1 dm3) is decreased on increasing the temperature. In other instances the increase in the temperature doesn t have an effect on kobs273. 

The syntheses of a variety of "multi-site" phase-transfer catalysts (PTCs) and the determination of their catalytic activity toward some simple Sn2 reactions and some weak nucleophile-weak electrophile SnAr reactions are described. In general, at the same molar ratio, the "multi-site" PTCs are as or more effective than similar "single-site" PTCs. Thus, the "multi-site" PTCs offer an economy of scale compared to "single-site" PTCs. 

We have recently reported ( ) several synthetic studies of weak nucleophile SnAr reactions. In the latter cases (26f-1), new synthetic methodology was reported for the direct introduction of fluoroalkoxy groups into a variety of aromatic systems. These reports represent synthetically useful procedures for obtaining some otherwise inaccessible fluoroalkoxy materials but, unfortunately, they require the use of a dipolar, aprotic solvent (usually hexamethylphosphoramide, HMPA) and, in some cases, elevated temperatures. However, because of their diverse and important applications ( ), the syntheses of these and other organofluoro compounds continue to be of interest. For example, two recent reports of useful fluoroalkoxy materials include the insecticide activity exhibited by fluoroalkoxy substituted 1,3,4-oxadiazoles... 

While the greatest percentage of PTC-aided anionic substitutions involve non-aromatic systems (7-10), a number of liquid-liquid and solid-liquid, PTC-aided SnAr reactions have been reported (32-38). These reports involve a variety of substrates [unactivated (32,33), slightly activated (M), activated (35-37), and transition metal complexed 32,38)1, nucleophiles OMe (32,38), CN ( ), SR (34) SCN (36), SO (36), OR (37)] and PTCs... 

Thus, PTC methodology can be effectively applied to a weak nucleophile SnAr reaction under a variety of PTC and reaction conditions. This may prove to be particularly useful for fluoroalkoxylation. That is, we have recently demonstrated (26h) that 2,2,2-trifluoroethoxide ion reacts under HMPA solvent conditions at or near room temperature with an extended range of substrates which contain a more active leaving group (nitro) than chloro. The former reaction occurs usefully even for substrates containing the weakly activating amido functionality. Similiar reactions may be possible for these substrates under PTC conditions. 

Also known as Meisenheimer-Jackson salt, the stable intermediate for certain SNAr reactions. 

Natural fluorine consists entirely of the isotope F and fluorine isotope effects (F KIE) are expected to be small. They were measured for the first time in 1993 [45] in the SNAr reaction of i F/ F fluorodinitrobenzenes with piperidine (Scheme 2). Their value (1.0262 0.0007) [45, 60] suggests a substantial C-F bond breaking in the rate-limiting step of the reaction. 

Cristau P, Vors JP, Zhu JP (2006) Rapid synthesis of cyclopeptide alkaloid-like para-cyclophanes by combined use of Ugi-4CR and intramolecular SNAr reaction. Qsar Comb Sci 25 519-526... 

Although 1,2-diazinamines are not very nucleophilic by themselves the nucleophilicity can be increased via initial deprotonation with strong base. This strategy has been followed by Heinisch and co-workers when studying intramolecular SNAr reactions (Equations 22 and 23) <1997H(45)673, 1997AP29>. 

BENZOFUSED HETEROCYCLES VIA SOLID-PHASE SnAR REACTIONS... 

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