Nucleophilic substitution synthetic applications

The large rate enhancements observed for bimolecular nucleophilic substitutions m polai aprotic solvents are used to advantage m synthetic applications An example can be seen m the preparation of alkyl cyanides (mtiiles) by the reaction of sodium cyanide with alkyl halides... 

The first widely used intermediates for nucleophilic aromatic substitution were the aryl diazonium salts. Aryl diazonium ions are usually prepared by reaction of an aniline with nitrous acid, which is generated in situ from a nitrite salt.81 Unlike aliphatic diazonium ions, which decompose very rapidly to molecular nitrogen and a carbocation (see Part A, Section 4.1.5), aryl diazonium ions are stable enough to exist in solution at room temperature and below. They can also be isolated as salts with nonnucleophilic anions, such as tetrafluoroborate or trifluoroacetate.82 Salts prepared with 0-benzenedisulfonimidate also appear to have potential for synthetic application.83... 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

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. 

Organosulfur chemistry is presently a particularly dynamic subject area. The stereochemical aspects of this field are surveyed by M. Mikojajczyk and J. Drabowicz. in the fifth chapter, entitled Qural Organosulfur Compounds. The synthesis, resolution, and application of a wide range of chiral sulfur compounds are described as are the determination of absolute configuration and of enantiomeric purity of these substances. A discussion of the dynamic stereochemistry of chiral sulfur compounds including racemization processes follows. Finally, nucleophilic substitution on and reaction of such compounds with electrophiles, their use in asymmetric synthesis, and asymmetric induction in the transfer of chirality from sulfur to other centers is discussed in a chapter that should be of interest to chemists in several disciplines, in particular synthetic and natural product chemistry. 

The nucleophilic vinylic substitution (S mV) of heteroatom-substituted alkylidene Meldrum s acids has been intensively studied and kinetics of the reaction <1998JOC6266, 1999CJC584, 2004JOC9248> as well as synthetic applications have been reported <19978567, 2002JHC15, 2005EJ04870> (cf. Section 8.11.4.2, Scheme 10). The preparation of the substrates and a sample application is shown in Scheme 90 <2001J(P2)1534>. 

A most important property of enolate anions, at least as far as synthesis is concerned, is their excellent nucleophilicity, which enables them to add to double bonds and to participate in nucleophilic substitution. When the addition is to a carbonyl double bond, it is called an aldol addition (Equation 17-4). Additions of enolate anions to carbon-carbon double bonds usually are classified as Michael additions (Equation 17-5), and these are discussed in Sections 17-5B and 18-9D. The principles of SN nucleophilic reactions of enolate anions (Equation 17-6) will be considered in Section 17-4, and their synthetic applications in detail in Chapter 18. 

The major focus in this chapter will be on synthesis, with emphasis placed on more recent applications, particularly those where regiochemistry and stereochemistry are precisely controlled. The reader is referred to the earlier reviews for full mechanistic information and details of historic interest. Electrophilic addition of X—Y to an alkene, where X is the electrophile, gives products with functionality Y (3 to the heteroatom X. Further transformations of X and/or Y provide the basis for diverse synthetic applications. These transformations include replacement of Y by hydrogen, elimination to form a ir-bond (either including the carbon bonded to X or (3 to that carbon so that X is now in an allylic position), and nucleophilic or radical substitution. Representative examples of these synthetic methods will be given below. This chapter will include examples of heterocycles formed in one-pot reactions where the the initial alkene-electrophile adduct contains an electrophilic group that can react further. Examples of heterocycles formed in several steps from alkene-electrophile adducts will also be considered. Cases in which activation by an external electrophile directly results in addition of an internal heteroatom nucleophile are treated in Chapter 1.9 of this volume. 

These heterocyclization reactions provide initial products with a functionality (3 to the heteroatom, except for cases where a proton is the electrophile. Synthetic applications often depend upon further transformation of this functionality. Useful transformations include replacement by hydrogen, elimination to form a ir-bond, nucleophilic substitution, and substitution via radical intermediates. These reactions will be discussed only when understanding the cyclization step requires inclusion of the functional group transformation. 

Dehydroheteroarenes like (10) and (11) have also been proposed as intermediates in nucleophilic substitution.23-25 Some of these reactions were evaluated uncritically and operation of other mechanisms like addition-elimination (AE) and ring opening-ring closure (ANRORC) can now be demonstrated in many such cases. Nevertheless, there is conclusive evidence for heteroaryne intermediacy in some reactions of heterocyclic halides. From the preparative point of view, nucleophilic coupling of such intermediates has found only limited applications.26-28 Reactive intermediates with an additional formal bond between nonadjacent atoms, like (12) and (13), have also been postulated but again hold little synthetic interest. 

The synthetic application of vicarious nucleophilic substitution, whereby hydrogen of an electrophilic arene is replaced by an a-functionalized alkyl substituent, has been reviewed 177 the sequence usually involves attack on a nitroalkene by a carbanion containing a leaving group X at the carbanionic centre, /i-elimination of HX from the er-adduct, and rearomatization on subsequent protonation. 

The electrophilic activation of a C—C multiple bond as a result of coordination to an electron-deficient metal ion is fundamental to much of organometallic chemistry, both conceptually and in synthetic applications (11). The Wacker process, a classic example of an efficient catalytic oxidation, is an important industrial reaction, used for the conversion of ethylene into acetaldehyde. The catalytic reaction begins with the coordination of ethylene to a Pd(ll) center, leading to activation of the ethylene moiety. The key step is the reaction of the metal-olefin complex with a nucleophile to give substituted metal-alkyl species (12). The integration of this reaction into a productive catalytic cycle requires the eventual cleavage of the newly generated M—C bond. 

Ionic liquids can be used as replacements for many volatile conventional solvents in chemical processes see Table A-14 in the Appendix. Because of their extraordinary properties, room temperature ionic liquids have already found application as solvents for many synthetic and catalytic reactions, for example nucleophilic substitution reactions [899], Diels-Alder cycloaddition reactions [900, 901], Friedel-Crafts alkylation and acylation reactions [902, 903], as well as palladium-catalyzed Heck vinylations of haloarenes [904]. They are also solvents of choice for homogeneous transition metal complex catalyzed hydrogenation, isomerization, and hydroformylation [905], as well as dimerization and oligomerization reactions of alkenes [906, 907]. The ions of liquid salts are often poorly coordinating, which prevents deactivation of the catalysts. 

---