Substitution elimination, sequential reactions

Recently, elegant synthesis of awft -MRS carbapenum has been reported. Sequential reaction of nitromethane via conjugate addition-elimination to a,P-unsaturated esters followed by Pd-catalyzed substitution of the resulting allyl nitro compound with the naphthosultam affords the allylation product which is an anti (Eq. 7.20).22... 

That ends this chapter on elimination reactions. It is apparent from the foregoing discussion that elimination reactions are far less well defined than either the substitution or addition reactions that we had studied previously. However, it was still possible to rationalise the production of the experimentally observed products. We will now look at sequential reactions, in which an addition reaction is followed by an elimination, or vice versa, and so leads to an overall substitution reaction... 

Nucleophilic substitution at an sp carbon usually proceeds via an addition/ elimination sequential pathway. Thus, the reaction of ArS- to, say, 1,1-dichloroethene, in the presence of a catalytic amount ethoxide anion, proceeds via an addition followed by a double elimination, with finally a further addition to yield the 1,2-dithiophenoxy derivative. 

Another potentially powerfnl sequence arises by combining one or two intramolecular Heck-type couplings with an intra- or intermolecular Diels-Alder addition (for early examples of inter-intermolecular one-pot domino Heck-Diels-Alder reactions see Refs. [49] and [50]). An all-intramolecular version of such a sequence has been shown to proceed reasonably smoothly for terminally alkoxycarbonyl-substituted 2-bromotrideca-l,ll-dien-6-ynes under palladium catalysis at 130 °C. At 80 °C, the sequential reaction stops after the two consecutive Heck-type cyclizations and subsequent /3-hydride elimination to give a 1,3,6-triene apparently only the ( )-isomer undergoes the intramolecular Diels-Alder reaction, as the (Z)-l,3,6-triene is observed accompanying the tetracyclic system obtained at 130 °C (Scheme 36). 

Iwao et d. introduced an efficient methodology ftH the synthesis of 3,4-disubstituted indoles 113 (57). Their strategy comprises two sequential steps 1) selective functionalization of l-silyl-3-dimethylaminomethylindole (111) at the 4-position by directed lithiation, followed by quenching with electrophiles, for the preparation of 4-dimethylamino-substituted indole 112 (58) 2) substitution of the dimethylamino group of 112 for various nucleophiles giving 113 upon desilylation through quatemization followed by a fluoride ion-induced elimination-addition reaction (Scheme 17) (59). 

The chloro groups of 4,7-dichloro-l,2-diazocines (vide supra) can be sequentially substituted by O-, S- or W-nucleophiles.25 27 The reaction most likely proceeds via an elimination-addition mechanism utilizing the valence tautomeric diazabicyclo[4.2.0]octatriene forms. 

Reaction of DMSB with triphenylsilyl-substituted oxiranyllithium leads to the formation of an olefinic silanol via sequential (1) coordination to the silicon, (2) Si-C bond migration, and (3) Peterson-type Si-O elimination to furnish the alkene. A pentacoordinate siliconate intermediate is presumably involved in this transformation. Therefore, it was reasonable to expect that addition of a nucleophile (methyllithium or lithium t>-propoxide) to an oxiranyl-substi-tuted SCB, which could generate a similar intermediate, would induce the C-Si bond migration to form the same silacyclopentane. Indeed, this alternative order of addition sequence provides the corresponding silanol with better efficiency (84% yield vs. 44%, Scheme 36). 

The A-nitroimidazolcs are stable for a time even in the presence of water, but treatment with concentrated sulfuric acid cleaves the N-nitro group, and strong base opens the ring. Much of the interest in such compounds is related to their multistep complex substitution reactions in which sequential nucleophilic addition of arylamines, ring opening, ring closure, nitroamide elimination, and rearomatization gives l-aryl-4-nitroimidazoles, e.g., 840 839. This method can also be used to prepare isotopically labeled imidazoles when labeled amino acids are used as the amine. 

For example, the thermal reactions of Os6(CO),8 with CO (56, 425) and P(OMe)3 (56, 98, 392) lead to the open raft species Osg(CO)2i and [Os6(CO)2i ) P(OMe)3 J (n = 1-6), respectively, probably by sequential bond hssion in the bicapped tetrahedral cluster. As indicated in Scheme 21, under slightly different reaction conditions, elimination of an osmium vertex occurs, resulting in the formation of clusters containing a trigonal-bipyrami-dal metal framework. These react further with nucleophiles to give open Osj clusters and finally substituted triosmium species. Cluster unfolding has also beeen observed in the reactions of Os5(CO),jH2 with a variety of nucleophiles (Scheme 22). 

Organometallic substitution of iron-complexed dioxolenes has been reported. The reaction proceeds with net inversion of configuration, the result of a two-step addition-elimination pathway. Dialkyl-cuprates, higher order cyanocuprates and Grignard reagents have all been employed, and sequential dis-... 

The M—A bond which is formed frequently shows a reactivity toward addition and substitution reactions similar to that of the original bond to the metal sequential combinations of the elementary processes of addition, substitution, and elimination are useful in synthesis, especially for organotin derivatives. The individual reactions, and their most important combinations are ... 

A third mechanism for substitution at C(sp3)-X bonds under basic conditions, elimination-addition, is occasionally seen. The stereochemical outcome of the substitution reaction shown in the figure tells us that a direct Sn2 substitution is not occurring. Two sequential Sn2 reactions would explain the retention of stereochemistry, but the problem with this explanation is that backside attack of MeO- on the extremely hindered top face of the bromide is simply not reasonable. The SrnI mechanism can also be ruled out, as the first-row, localized nucleophile MeO- and the 2° alkyl halide are unlikely substrates for such a mechanism. 

As well as those reactions that fall neatly into one or other of the three simple reaction types, there are some reactions where an addition reaction is followed by an elimination reaction, or vice versa, resulting in an overall substitution of a group. These reactions will be considered separately in this book under the heading of sequential addition/elimination reactions. 

Nitration of 6-substituted purines at C-2, using a mixture of tetra-n-butylammonium nitrate and trifluo-roacetic anhydride, is an exceptionally useful functionalisation of the purine ring system. The reaction works for both electron-rich (adenosine), 6-alkoxypurines and electron-poor (6-chloropurine) substrates, but full protection of all OH and NH groups is required. This is not a simple electrophihc substitution - the mechanism has been shown, using 6-chloro-9-Boc purine, to involve sequential nitration of N-7, addition of trifluoroacetoxy at C-8 and then migration of the nitro group to C-2. The final, re-aromatisation, step involves elimination of trifluoroacetic acid. Displacement of a 2-nitro group, thus introduced, by fluoride as nucleophile (see 27.5 for nucleophilic substitutions) can be made the means to synthesise 2-fluoroadenosine. ... 

Ketyls generated by the reaction of SmE with aldehydes and ketones have been incorporated into numerous sequential processes in which a radical reaction is involved. Sequential radical processes, radical cyclization/carbonyl additions, radical cyclization/substitution reactions, nucleophilic acyl substitution/radical cyclizations, cyclization/elimination processes, and others have all been realized. Because these types of reactions have been extensively reviewed [2b, 25], further details will not be given here. Needless to say, new sequential processes based on SmE-promoted ketyl/olefin coupling reactions are still being developed (Eq. 75) [88]. 

Many attempts at other modifications of poly(vinyl chloride) were reported in the literature. Often, the reactions are based on expectations that the polymers will react like typical alkyl halides. Unfortunately, in place of nucleophilic substitutions, the polymers often undeigo rapid and sequential eliminations of HCl along the chains. Nevertheless, many substitution reactions are still possible and can be successfully carried out. One example is a replacement of 43% of the chlorine atoms with azide groups... 

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