Tsuji consolation response

The Tsuji-Trost reaction or Trost allylation , also often simply called allylic alkylation , is a name reaction from the field of organic chemistry . It is a palladium- catalyzed alkylation of allyl compounds . It mostly serves to introduce alcohols , amines or derivatives of phenol . The starting materials required are compounds which have a leaving group in the allylic position. It was named after Jiro Tsuji and Barry Trost .

Reaction mechanism

First, the alkene used forms a π complex with the palladium catalyst . In an oxidative addition, an η ³ -π-allyl complex is formed with inversion and elimination of the leaving group . This step is also known as ionization. Depending on the hardness of the nucleophile , one of two further reactions takes place:

In the case of soft nucleophiles, which are formed by conjugated acids with a pK _a value of less than 25, the nucleophile usually adds directly to the allyl. The nucleophilic addition takes place again with inversion. During the subsequent ligand dissociation, the alkylated allyl is released and the catalyst is regressed.

Educts and Catalysts

Consolation ligand

The required palladium catalyst of oxidation level 0 is generated in situ . When ligands are suitable phosphine ligand , for example, the Trost ligand or triphenylphosphane .

All allyls with electron-poor, i.e. good leaving groups, such as acetates or bromides , can be used as allylic starting materials . When carbonates are used as a leaving group, there is also no need to use an additional base ( build in base ). Activated methylenes, enolates, amines or phenols, for example, can be used as nucleophiles.

Water can be used as a nucleophile to introduce hydroxyl groups , and ethers can be obtained using alcohols. Phthalimide salts are suitable for introducing amines . The desired amine can be released from the product obtained in a further reaction step.

Asymmetric response

For the asymmetric Tsuji-Trost reaction, also known as Trost's asymmetric allylic alkylation , metal complexes with enantiomerically pure chiral ligands are used as catalysts. In the reaction there is an inversion at the stereocenter .

The reaction has been used, among other things, as a key enantioselective step in the total synthesis of galantamine and morphine .

Modification of the asymmetric reaction

The complementary reaction was developed by Günter Helmchen . Using iridium catalysts with chiral phosphoramidite ligands, chiral terminal alkenes can be synthesized from achiral internal alkenes. In contrast to the Trost allylation, the nucleophile does not attack the position that was carried by the leaving group, which is due to the different electronic properties of palladium and iridium. Carboxylic acid anions can also be used as leaving groups, but organic carbonates are mostly used. Similar reactions can also be carried out with molybdenum and iridium catalysts. In contrast to the Tsuji-Trost reaction, these reactions also offer access to branched regioisomers .

Individual evidence

1. ↑ BM Trost, Pure Appl. Chem. 1981 , 53 , 2357 ( PDF ).
2. ↑ J. Tsuji, Pure Appl. Chem. 1982 , 54 , 197 ( PDF ).
3. ^ BM Trost, TJ Fullerton: New synthetic reactions. Allylic alkylation. , in: J. Am. Chem. Soc. 1973 , 95 , 292-294.
4. ^ BM Trost, TJ Dietsch: New synthetic reactions. Asymmetric induction in allylic alkylations. , in: J. Am. Chem. Soc. 1973 , 95 , 8200-8201.
5. ^ BM Trost, PE Strege: Asymmetric induction in catalytic allylic alkylation. , in: J. Am. Chem. Soc. 1977 , 99 , 1649-1651.
6. ^ BM Trost, ML Crawley: Asymmetric Transition-Metal-Catalyzed Allylic Alkylations: Applications in Total Synthesis , in: Chem. Rev. 2003 , 103 , 2921-2944.
7. ^ BM Trost, W. Tang, FD Toste: Divergent Enantioselective Synthesis of (-) - Galanthamine and (-) - Morphine. , in: J. Am. Chem. Soc. 2005 , 127 , 14785-14803.
8. ↑ JP Janssen, G. Helmchen: First Enantioselective Alkylations of Monosubstituted Allylic Acetates Catalyzed by Chiral Iridium Complexes , in: Tetrahedron Lett. 1997 , 109 , 8025-8026.
9. ↑ B. Bartels, G. Helmchen: Ir-catalysed allylic substitution: mechanistic aspects and asymmetric synthesis with phosphorus amidites as ligands , in: Chem. Commun. 1999 , 741-742.
10. ↑ G. Lipowsky, N. Miller, G. Helmchen: Regio- and enantioselective iridium-catalyzed allylic alkylation with in situ activated P, C-chelate complexes , in: Angew. Chem. 2004 , 116 , 4695-4698.
11. ↑ A. Leitner, C. Shu, JF Hartwig, Org. Lett. 2005 , 7 , 1093-1096.