Nucleophilic substitution avoided

Carbonates undergo nucleophilic substitution reactions analogous to chloroformates except in this case, an OR group (rather than chloride) is replaced by a more basic group. Normally these reactions are cataly2ed by bases. Carbonates are sometimes preferred over chloroformates because formation of hydrogen chloride as a by-product is avoided, which simplifies handling. However, the reactivity of carbonates toward nucleophiles is considerably less than chloroformates. 

Besides radical additions to unsaturated C—C bonds (Section III.B.l) and sulfene reactions (see above), sulfonyl halides are able to furnish sulfones by nucleophilic substitution of halide by appropriate C-nucleophiles. Undesired radical reactions are suppressed by avoiding heat, irradiation, radical initiators, transition-element ion catalysis, and unsuitable halogens. However, a second type of undesired reaction can occur by transfer of halogen instead of sulfonyl groups283-286 (which becomes the main reaction, e.g. with sulfuryl chloride). Normally, both types of undesired side-reaction can be avoided by utilizing sulfonyl fluorides. 

Phosphate esters have a variety of mechanistic paths for hydrolysis. Both C-O and P-0 cleavage are possible depending on the situation. A phosphate monoanion is a reasonable leaving group for nucleophilic substitution at carbon and so 8 2 or SnI reactions of neutral phosphate esters are well known. PO cleavage can occur by associative (by way of a pentacoordinate intermediate), dissociative (by way of a metaphosphate species), or concerted (avoiding both of these intermediates) mechanisms. 

The mechanistic aspects of nucleophilic substitution reactions were treated in detail in Chapter 4 of Part A. That mechanistic understanding has contributed to the development of nucleophilic substitution reactions as important synthetic processes. Owing to its stereospecificity and avoidance of carbocation intermediates, the Sw2 mechanism is advantageous from a synthetic point of view. In this section we discuss... 

Pyrimido[4,5-d]pyridazine-2,5-diones were synthesized in a similar manner, employing several hydrazines (R3 = H, Me, Ph) for the nucleophilic substitution prior to cyclative cleavage. Due to the high nucleophilicity of the hydrazines, reaction times for the substitution step could be reduced to 30 min. In the case of phe-nylhydrazine, concomitant cyclization could not be avoided, which led to very low overall yields of the isolated products. 

Many of these complications can be avoided when monosulfoxides are converted to the dications using triflic anhydride instead of concentrated sulfuric acid. This method was suggested by Furukawa et al.71 in 1987. Reaction of triflic anhydride with a monosulfoxide72 transforms it into trifluoromethanesulfonyloxysulfonium salt 47, which undergoes clean intramolecular nucleophilic substitution of trifluoromethylsulfonate anion by the other sulfur atom with formation of the disulfonium dication 34 in a high yield (Scheme 16).73... 

The base-promoted cyclisations have also been effected by electrogenerated tri-chloromethyl anion (Scheme 10) but in this case nucleophilic substitution is a significant competing reaction. This complication is avoided by the use of azobenzene as probase. 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

Deprotonation of sulfonates by strongly basic nucleophiles can be avoided by using arenesulfonates instead of alkanesulfonates. Arenesulfonates can, however, give rise to another type of side reaction aromatic nucleophilic substitution. Nitro-arenesulfonates are particularly prone to attack by a nucleophile at the arene [89, 90] (Scheme 4.19). 

Other problematic electrophiles are 2-(acylamino)ethyl halides and related compounds. Although numerous successful nucleophilic substitutions with such substrates have been described in the literature, occasionally a side reaction becomes dominant. If the leaving group is hard or if the reaction conditions chosen are conducive to the formation of carbocations, intramolecular O-alkylation of the electrophile will lead to the formation of oxazolines (Scheme 4.40). This cyclization can sometimes be avoided by choosing a softer leaving group. 

By choice of reaction conditions so as to avoid nucleophilic substitution, the diazonium salt from the 3-amine (126) will undergo diazo coupling to form azo dyes (79BRP1550828). 

Although epoxides, like bromonium ions, contain strained three-membered rings, they require either acid catalysis or a powerful nucleophile to react well. Compare these two reactions of a 1,1,2-trisubs tituted epoxide. They are nucleophilic substitutions related to those we introduced in Chapter 17 (p. 435) but in that chapter we carefully avoided discussing epoxides of the unsymmetrical variety. In this example, Vhe regiochemistry reverses with the reaction conditions. Why ... 

In a competition experiment between chiral N-sulfinyl oxazolidinone and Andersen s menthyl sulfinate ester, it has been shown that the former is at least two orders of magnitude more reactive than the latter. This finding is being used to avoid some of the problems involved in sulfinate esters, related to the nature of the alkoxide leaving group in the nucleophilic substitution. 

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