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Modyfikowane i alternatywne reagenty reakcji Mitsunobu

Kołodziejczyk A.S.

Wiadomości Chemiczne

2010

[Z] 64, 11-12

1073-1097

The Mitsunobu reaction provides an extremely useful and versatile synthetic route for a large array of products involving formation of a new C-O, C-N, C-S, C-X, or C-C bond. The reaction is a dehydrative coupling of an alcohol with an acid/pronucleophile using a combination of an oxidizing azo reagent and a reducing phosphine reagent -equation (1). The reaction is very popular due to its stereoselectivity and compatibility with a wide range of functional groups. However, the use of this method is complicated by the resulting complex reaction mixtures containing a product, triphenylphosphine oxide and the reduced azodicarboxylate, as well as unreacted starting material. Due to omnipresence of the Mitsunobu reaction, it was a subject of numerous reviews [1-12]. The mechanism and the stereochemical result of the reaction are still thoroughly studied [22-38] and the current, generally accepted mechanism is outlined in Scheme 1. This article provides an overview of the separation-friendly strategies introduced to facilitate product isolation in the Mitsunobu reaction and its modified and alternative mediators. As two comprehensive reviews devoted to modified Mitsunobu reagents and separation techniques facilitating isolation of the condensation product appeared fairly recently [7, 8], this work concentrates on examples of isolation-friendly strategies and studies subsequent to mentioned reviews. Separation facilitating strategies are based on tagging one of Mitsunobu reagents or substrates with a "separation tag" (phase tag, affinity tag), which controls the behaviour of the component and allows to separate the tagged reaction component from untagged ones. There are four main separation techniques used in the Mitsunobu reaction: polymerassisted phase-switching or solid phase immobilization (2.1.1.), acidic/basic aqueous work-up (2.1.2.), fluorous approach (2.1.3.), and post-reaction sequestration. Both phosphine and azodicarboxylate can be attached to insoluble polymer and the derived side-products (phosphine oxide or hydrazodicarboxylate) can be removed by filtration at the end of the reaction. Fluorous tagging makes possible the separation of a fluorous compound from nonfluorous ones either by partitioning between a fluorous and an organic liquid or by fluorous solid-phase extraction (FSPE) - Scheme 6. A fluorous-tagged acid was also applied to achieve inversion of an alcohol configuration (Scheme 8). Another separation-facilitating strategy uses polymerizable Mitsunobu reagents and post-reaction sequestration, e.g. by ring opening metathesis polymerization (ROMP), either of a condensation product (Scheme 9), or side products (impurity anihilation). The scope of the Mitsunobu reaction was greatly widened by introduction of alternative Mitsunobu reagents by the Tsunoda-Itô group [69-79]. Some of these reagents (1-4, Scheme 12) mediate C-alkylation reactions of very weak acids (pK_a > 23) [77, 78]. Several other modified Mitsunobu reagents are also described.

Alternatywne mediatory reakcji Mitsunobu

Falkiewicz B., Wiśniewski K., Kołodziejczyk A.S.

Wiadomości Chemiczne

2001

[Z] 55, 9-10

849-858

The Mitsunobu reaction is a versatile method for the alkylation of various Bronsted-Lowry acids (HA) by alcohols, proceeding in neutral media in a presence of the redox system which traditionally consists of diethyl azodicarboxylate and triphenylphosphine. The key step of the process proceeds according to the SN2 mechanism and results in one of the most useful attributes of the reaction, namely complete configurational inversion at the carbinol carbon. The reaction, however, has a serious limitation - the acidic component has to have pKa smaller than 13 for the reaction to proceed smoothly. Moreover, the classical methodology of the reaction suffers from low yields when applied to secondary alcohols. In recent years, in order to overcome these drawbacks and expand the versatility of the original combination of the Mitsunobu mediators, significant progress in the reaction methodology has been made, mainly due to the work of Tsunoda and Itô. Two types of new mediators have been developed to replace the azodicarboxylate-TPP system. The first one is an N,N,N',N'-tetrasubstituted azodicarboxamide - tributyl phosphine system. All azodicarboxamide derivatives were found to be more efficient than traditional DEAD in the Mitsunobu reaction, especially for less acidic HX. N,N,N',N'-Tetramethylazodicarboxamide, TMAD, gives the best overall results among acyclic amides, whereas 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetraazocin-3,8-dion, DHTD, in combination with TBP was found to be unique in mediating the formation of the C-C bond with sec-alcohols at room temperature. The other type of new mediators in the Mitsunobu reaction, structurally based on betaine, is cyanomethylenetrialkylphosphorane. The phosphorane reagents are generally less active at room temperature, but in higher temperatures they are, esp. CMMP, better than DHTD-TBP and afford satisfactory alkylation of secondary alcohols. Furthermore, the phosphorane reagents mediate the reaction of acids of pKa up to 23.5 [33]. Comparative studies of the C-alkylation revealed the general reactivity of new mediators as TMAD-TBP ( DHTD-TBP ( CMBP ( CMMP.