Introduction of Hindered Electrophiles via C–H Functionalization in a Palladium-Catalyzed Multicomponent Domino Reaction

Abstract

A general method for the incorporation of secondary alkyl iodides in a palladium-catalyzed multicomponent domino reaction is reported. With the relatively inexpensive Pd(OAc)₂ as the catalyst and norbornene as a mediator, a variety of 1,2,3-trisubstituted aromatic compounds were synthesized. The reaction was shown to be scalable, producing excellent isolated yields on up to 5 mmol scale. Chiral alkyl iodides were also incorporated without any loss of stereochemical information. The developed method offers an expedient and mild C–H functionalization strategy for the synthesis of sterically congested aromatic compounds in a one-pot process.

Key words

multicomponent reaction - palladium - Catellani reaction - domino reaction - C–H functionalization

• References


For recent reviews, see:
• 1a For palladium: Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
• 1b For rhodium: Colby DA, Bergman RG, Ellman JA. Chem. Rev. 2010; 110: 624
• 1c For ruthenium: Arockiam PB, Bruneau C, Dixneuf PH. Chem. Rev. 2012; 112: 5879

For reviews of the Catellani reaction, see:
• 2a Sui X, Zhu R, Gu Z. Synlett 2013; 24: 2023
• 2b Ferraccioli R. Synthesis 2013; 45: 581
• 2c Martins A, Mariampillai B, Lautens M. Top. Curr. Chem. 2010; 292: 1
• 2d Lautens M, Alberico D, Bressy C, Fang Y.-Q, Mariampillai B, Wilhelm T. Pure Appl. Chem. 2006; 78: 351
• 3a Weinstabl H, Suhartono M, Qureshi Z, Lautens M. Angew. Chem. Int. Ed. 2013; 52: 5305
• 3b Qureshi Z, Weinstabl H, Suhartono M, Lui H, Thesmar P, Lautens M. Eur. J. Org. Chem. 2014; 4053
• 4 Sui X, Zhu R, Li G, Ma X, Gu Z. J. Am. Chem. Soc. 2013; 135: 9318
• 5 Catellani M, Cugini F. Tetrahedron 1999; 55: 6595
• 6 Catellani M, Motti E, Minari M. Chem. Commun. 2000; 157
• 7 Rudolph A, Rackelmann N, Lautens M. Angew. Chem. Int. Ed. 2007; 46: 1485
• 8 Rudolph A, Rackelmann N, Turcotte-Savard M.-O, Lautens M. J. Org. Chem. 2009; 74: 289
• 9a Jutand A, Mosleh A. Organometallics 1994; 14: 1810
• 9b Amatore C, Carré E, Jutand A, M’Barki MA. Organometallics 1995; 14: 1818
• 10 Catellani M, Fagnola MC. Angew. Chem., Int. Ed. Engl. 1994; 33: 2421
• 11 Schaus SE, Brandes BD, Larrow JF, Tokunaga M, Hansen KB, Gould AE, Furrow ME, Jacobsen EN. J. Am. Chem. Soc. 2002; 124: 1307
• 12 Santaniello E, Casati S, Ciuffreda P, Gamberoni L. Tetrahedron: Asymmetry 2005; 16: 1705
• 13 Appel R. Angew. Chem., Int. Ed. Engl. 1975; 14: 801
• 14 We attempted to determine the absolute stereochemistry of the alkylated product but all efforts gave crystals that were not suitable for X-ray crystal analysis. Use of the Mosher esters confirmed the ee but assigning the stereochemistry was not definitive. We anticipate overall inversion of 3m occurred, in analogy to our previous work, however we do not have definitive proof in this case. See the Supporting Information for analysis of the Mosher method.
• 15 Larchevêque M, Mambu L, Petit Y. Synth. Commun. 1991; 21: 2295
• 16 For a recent review of C–N coupling, see: Surry DS, Buchwald SL. Chem. Sci. 2011; 2: 27