Titanium Isopropoxide as Efficient Catalyst for the Aza-Baylis−Hillman Reaction. Selective Formation of α-Methylene-β-amino Acid Derivatives

Abstract

The direct formation of alpha-methylene-beta-amino acid derivatives is achieved using the aza version of the Baylis-Hillman protocol. The products are readily formed in a three-component one-pot reaction between arylaldehydes, sulfonamides, and alpha,beta-unsaturated carbonyl compounds. The reaction is efficiently catalyzed by titanium isopropoxide and 2-hydroxyquinuclidine in the presence of molecular sieves. The protocol allows for structural variation of the substrates, tolerating electron-poor and electron-rich arylaldehydes and various Michael acceptors.

The Morita-Baylis-Hillman Reaction: Insights into Asymmetry and Reaction Mechanisms by Electrospray Ionization Mass Spectrometry

“…Using this three-component one pot system yields and chemoselectivity of the aza-adducts was improved. Furthermore, yields over 94% and selectivity reaching 99% were obtained in reaction times around 6 h ( Scheme 7 ) [ 20 ].…”

“…The diversity of chiral catalysts tested included Lewis acids and Lewis bases, Bronsted acids, thioureas, bulky ammonium salts, ionic liquids and phosphines [ 4 ]. Of those organocatalyst employed for asymmetric MBH reactions, bifunctional organocatalysts via hydrogen bonding has been of great interest in the last years, and specially for the aza-MBH reaction, the compounds isocupreidine [ 20 ], phosphinyl BINOLs [ 23 ], and ( S )-3-( N -isopropyl- N -3-pyridinylaminomethyl) BINOL [ 24 ] are the most efficient bifunctional catalysts employed so far. Several asymmetric MBH reactions were reported, and two reviews regarding asymmetric MBH reactions were recently published [ 4 , 7 ], so we will mention some important and recent advances in this field.…”

Privileged chiral catalysts in asymmetric Morita-Baylis-Hillman/aza-Morita-Baylis-Hillman reaction

“…Having successfully developed a one-pot, threecomponent aza-MBH reaction [29,30], they implemented enantioselectivity in their protocol by replacing DABCO with cinchona derivatives [31]. N-Sulfonyl imines, formed in situ from tosylamide and an aldehyde (in the presence of a small amount of titanium 2-propoxide and molecular sieves), reacted with methyl acrylate in the presence of -ICD (4, 15 mol%) to yield the aza-MBH adducts in variable yields (12% 95%) and with moderate enantiomeric excesses (49% 74% ee).…”

Aza‐Baylis–Hillman Reactions and Their Synthetic Applications

“…Subsequently, they found that use of Ti(OiPr) 4 as the Lewis acid co-catalyst was superior to that of La(OTf) 3 , giving better chemoselectivity in the aza adducts 3. [27] Scheme 23.…”