What Is the Baylis-Hillman Reaction?
The Baylis-Hillman reaction, also known as the Morita-Baylis-Hillman reaction, is a reaction between an α,β-unsaturated compound and an electrophilic reagent (aldehyde, ketone) in the presence of a suitable catalyst to produce an α-addition product of an olefin. Later, the electrophilic reagent was extended to electrophilic reagents of sp2 carbon of imines, which was called the aza-Baylis-Hillman reaction.
The electrophilic reagent in the substrate can be an aldehyde, imine, imine salt, and activated ketone. The α,β-unsaturated compound (activated olefin) can be an electron-deficient olefin such as acrylate, acrolein, vinyl ketone, acrylonitrile, α,β-unsaturated sulfone, sulfoxide, imine, and α,β-unsaturated cycloalkenone. The catalyst is generally DABCO, but other weak nucleophiles such as tertiary amines and tertiary phosphines can also be used to catalyze this reaction.
Fig 1. Baylis-Hillman reaction.
Reaction Mechanism of Baylis-Hillman Reaction
The reaction undergoes an addition-elimination reaction process initiated by the Michael addition reaction of tertiary amine and activated olefin.
Fig 2. The mechanism of the Baylis-Hillman reaction. [1]
The Baylis-Hillman reaction has the following characteristics:
- The reaction raw materials are cheap and easy to obtain;
- The reaction is atom-economical;
- The products generated by the reaction have multiple functional groups that can be further transformed;
- It is environmentally friendly. The catalysts of the reaction are mainly small organic molecules, thus avoiding the metal ions that may be used in conventional asymmetric catalytic reactions;
- The reaction conditions are mild, and most reactions can be carried out at room temperature.
Application Examples of Baylis-Hillman Reaction
In recent years, the Baylis-Hillman reaction has made great progress in mechanism research and asymmetric catalysis controlled by chiral reagents. At present, the catalysts successfully used for asymmetric Baylis-Hillman reaction are mainly some difunctionalized tertiary amines and tertiary phosphine compounds. In addition to having a nucleophilic functional group, these catalysts also have active hydrogen as a hydrogen bond donor. In addition to chiral catalysts, chiral co-catalysts and non-chiral tertiary amine or tertiary phosphine co-catalyst systems have also been successfully used in asymmetric Baylis-Hillman reactions with good results.
- Example 1: In various asymmetric catalytic Baylis-Hillman reactions, the reaction of sulfonyl imide and various activated olefins achieved excellent yields and ee values [2].
- Example 2: Since the product of the Baylis-Hillman reaction is a highly functionalized compound, the reaction has broad application prospects in synthesis. Many papers have reported methods for further transformation of the Baylis-Himan reaction product to synthesize key skeleton structures. For example, the Jacobsen group carried out various derivatizations on the aza-Baylis-Hillman reaction product to prepare a variety of synthetically valuable intermediates [3].
- Example 3: The Corey group used the intramolecular Baylis-Hillman reaction as a key step to complete the total synthesis of the natural product salinospo-ramide A analogues [4].
Fig 3. Synthetic examples via Baylis-Hillman reaction.
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References
- Hill, J. S., lsaacs, N. S., J. Phys. Org. Chem. 1990, 3 ,285.
- Shi, M., Chen, L. H., Li, C. Q., J. Am. Chem. Soc. 2005, 127, 3790.
- Raheem, I. T., Jacobsen, E. N. Adv. Synth. Catal. 2005, 347, 1701.
- Reddy, L. R., Fournier, J. F., Reddy, B. V. S., Corey, E. J., Org. Lett. 2005, 7, 2699.
