Halide and Sulfonate Substitution

HMPA or NMP JOC 48 1360 (1983) (1°, 2° alkyl bromide and iodide 2° alkyl tosylate allylic chloride) 

18-crown-6/H20 TL 3183 (1975) (1 alkyl, allylic, benzylic bromides 2° alkyl tosylate 2 allylic mesylate) 31 7509 (1990) (2 allylic bromide) IOC 58 385 (1993) (2° alkyl inflate) 

Mg/MoOj-py-HMPA IOC 42 1479 (1977) (aryl bromides) Austral I Chem 31 2091 (1978) (1°, 2°, 3° alkyl bromides aryl bromides) 

Ph2SbSbPh2, hv/H202, NaOH IACS 113 8177 (1991) (1° alkyl iodides) 

2-pyrrolidinone H2S04, S03/H20 AgN03, H20 Ag20, H20 LiOH, H20 NaOH, (n-Bu4N)HS04 

Syn 793 (1981) (1° alkyl chloride, bromide, iodide 1° allylic bromide 1° benzylic chloride, bromide) 

B2H6/H202, NaOH Ph2SbSbPh2, hv/H202f NaOH air, n-Bu3SnH/NaBH4 

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Fonnation of allylic products is characteristic of solvolytic reactions of other cyclopropyl halides and sulfonates. Similarly, diazotization of cyclopropylamine in aqueous solution gives allyl alcohol. The ring opening of a cyclopropyl cation is an electrocyclic process of the 4 + 2 type, where n equals zero. It should therefore be a disrotatory process. There is another facet to the stereochemistry in substituted cyclopropyl systems. Note that for a cri-2,3-dimethylcyclopropyl cation, for example, two different disrotatory modes are possible, leading to conformationally distinct allyl cations ... 

Propargylic acetates, halides, and sulfonates usually react with a double-bond shift to give allenes.34 Some direct substitution product can be formed as well. A high ratio of allenic product is usually found with CH3Cu-LiBr-MgBrI, which is prepared by addition of methylmagnesium bromide to a 1 1 LiBr-Cul mixture.35... 

Allylic stannanes can be prepared from allylic halides and sulfonates by displacement with or LiSnMe3 or LiSnBu3.146 They can also be prepared by Pd-catalyzed substitution of allylic acetates and phosphates using (C2H5)2AlSn... 

Direct nucleophilic displacement of halide and sulfonate groups from aromatic rings is difficult, although the reaction can be useful in specific cases. These reactions can occur by either addition-elimination (Section 11.2.2) or elimination-addition (Section 11.2.3). Recently, there has been rapid development of metal ion catalysis, and old methods involving copper salts have been greatly improved. Palladium catalysts for nucleophilic substitutions have been developed and have led to better procedures. These reactions are discussed in Section 11.3. 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

Alkylation of hydroxylamine with primary halides and sulfonates is rarely used nowadays for preparation of A-alkylhydroxylamines due to the competing formation of N,N-dialkylhydroxylamines. A number of older procedures have been reported with low to moderate yields of Al-alkylhydroxylamines. Yet, in many cases the reported low yields can be attributed to workup losses during distillation and crystallization steps rather than to the polyalkylation. Use of excess of hydroxylamine in reactions with primary alkyl halides (e.g. 3) improves the yields of monoalkylation (equation 2). Most of the examples of alkylation of hydroxylamine in good yield involve a substitution of an activated halogen atom at benzylic positions as well as in haloacetamides 4 leading to alkylhydroxylamines such as 5 where dialkylation rates are lower (equation 3). 

Nucleophilic substitution of halogen atom in aromatic and heteroaromatic halides with a hydroxyamino group proceeds only in substrates that are activated by a strong electron-withdrawing substituent in the benzene ring (e.g. 27, equation 17). Despite this limitation this reaction is useful for synthesis of arylhydroxylamines and usually provides good yields of products. Along with activated aryl halides and sulfonates, activated methyl aryl ethers such as 28 can be used (equation 18). 

The general method for the preparation of organo-fluorine compounds from halides and sulfonates using anhydrous TBAF suffers from the fact that wherever possible an elimination reaction occurs decreasing the yield of the fluoro-substituted product. Traces of moisture present in anhydrous TBAF induce the formation of a hydroxy-substituted product. 1-Bromooctane... 

The facility of arene reductive elimination underpins numerous C-C, C-O and C-N bond-forming reactions, which may be catalysed by late transition metals, in particular palladium (Figure 4.10). Although there are many variants, the general reaction scheme involves introduction of the aryl in electrophilic form via oxidative addition of an aryl halide (or sulfonate), substitution of the palladium halide by a nucleophile (which may also be carbon based) followed by reductive elimination. It is noteworthy that nucleophilic aromatic substitution in the absence of such catalysts can be difficult. 

The lone pairs may act as nucleophiles in substitution reactions of alkyl halides and sulfonates, in the solvolysis of epoxides, and in addition reactions to carbonyl groups. These reactions often proceed with acid or base catalysis. 

The conjugate base of an alkyne is an alkyne anion (older literature refers to them as acetylides), and it is generated by reaction with a strong base and is a carbanion. It funetions as a nucleophile (a source of nucleophilic carbon) in Sn2 reactions with halides and sulfonate esters. Acetylides react with ketones, with aldehydes via nucleophilic acyl addition and with acid derivatives via nucleophilic acyl substitution. Acetylides are, therefore, important carbanion synthons for the creation of new carbon-carbon bonds. Some of the chemistry presented in this section will deal with the synthesis of alkynes and properly belongs in Chapter 2. It is presented here, however, to give some continuity to the discussion of acetylides. 

Once again, the nickel-catalysed reactions are far more sensitive to the steric encumbrances, than the palladium-catalysed analogues. Aryl triflates and related sulfonates can serve as the electrophilic reactants in the Kharasch reactions in the presence of an equimolar amount of lithium bromide. The latter additive is a reagent for triflate-bromide exchange, which became a very fast reaction under the Kharasch reaction conditions, since the nickel and palladium-catalysed nucleophilic substitutions of aryl halides and sulfonates are well established reactions, see Chapter 3. In this manner, 2-biphenyl triflate (135) was reacted with 4-tolylmagnesium bromide (136) to give 2-(4-tolyl)biphenyl (137) with a 93% yield [40], respectively. Scheme 8. 

Many other types of organic compounds can be conveniently prepared by nucleophilic substitution processes. These are exemplified in Scheme 5.4. It should be noted that the processes most used for synthetic transformations involve substrates that are reactive in the direct-displacement mechanism, i.e., primary and unhindered secondary alkyl halides and sulfonates. The tendency toward elimination in tertiary alkyl systems is sufficiently pronounced to limit the usefulness of nucleophilic substitution reactions in synthetic transformations involving these systems. 

Oxidative addition of substrates possessing C-X or H-X bonds of medium polarity and of substrates possessing Ar-X bonds that cannot undergo S 2 pathways often occur by concerted pathways involving three-centered transition states more like those of the oxidative additions of nonpolar substrates. The clearest cases in which reactions occiu by concerted pathways are the oxidative additions of aryl halides and sulfonates to paUadium(0) complexes. These reactions have been studied extensively because they are the first step of transition-metal-catalyzed nucleophilic aromatic substitution reactions called cross couplings. The oxidative additions of the O-H and N-H bonds in water, alcohols, and amines also appear to occur by concerted three-centered transition states in many cases. 

Catalytic nucleophilic substitution reactions comprise some of the most commonly used catalytic processes in S)mthetic organic chemistry. Substitutions at aromatic and vinylic halides and sulfonates, sho vn generically in Equation 19.1, are commonplace in the preparation of pharmaceutical candidates, have often been used in the s)mtheses of natural products, and have been used many times in the syntheses of sophisticated conjugated organic materials. These metal-catalyzed reactions are typically called cross-coupling reactions. ... 

Copper complexes have been used as reagents and as catalysts for the formation of carbon-carbon bonds. The most utilized reactions mediated by copper have been couplings of alkyl halides and sulfonates because copper complexes were unique for many years as reagents that would mediate the nucleophilic substitution of alkyl and aryl nucleophiles with alkyl halides. In recent years, work has been conducted to develop copper-catalyzed versions of cross couplings with aryl halides to address the issues of the cost of palladium catalysts. Although few examples of these processes currently rival those catalyzed by palladium complexes, they do illustrate the potential of copper complexes to catalyst these types of cross-coupling processes. 

The C-X bond of alkyl halides and sulfonate esters is polarized such that the carbon has a positive dipole. Halides and sulfonate anions are good leaving groups. Nucleophiles attack primary and secondary alkyl halides, displacing the leaving group in what is known as aliphatic, bimolecular nucleophilic substitution, the Sn2 reaction. The 8 2 reaction follows second-order kinetics, has a transition state rather than an intermediate, and proceeds via back-side attack of the nucleophile on the halide and inversion of configuration. 

Preparation of Halides and Sulfonate Esters by Substitution Reactions... 

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