Recent Advances in the Baylis−Hillman Reaction and Applications

The baylis-hillman reaction : a novel carbon-carbon bond forming reaction

2.3.3. Fluorinated Imines 7 2.3.4. Arylimino Acetates 8 2.3.5. In Situ Generated Iminium Ions 8 2.4. -Substituted Michael Acceptors 8 2.5. Formation of Unexpected Products 10 2.5.1. Reaction with Cyclic Enones 11 2.5.2. Reaction with Vinyl Ketones 11 2.5.3. Reaction with Acrolein 12 2.5.4. Reaction with Activated Allenes and Alkynes 12 2.5.5. Reaction of Salicyl N-Tosylimines 12 3. Stereoselective Synthesis 13 3.1. Use of Chiral Aldehydes 13 3.2. Use of Chiral Bases 13 3.3. Use of Chiral Phosphines 16 3.4. Use of a Chiral Sulfide 18 3.5. Use of an Organocatalyst Derived from BINOL 18 3.6. Use of a Chiral Ligand Derived from Thiourea 18 3.7. Use of Chiral Ionic Liquids 18 4. Alternative Access Pathways to -Aminocarbonyl Compounds 18

aza-Baylis−Hillman Reaction

A new protocol for the syntheses of (E)-3-benzylidenechroman-4-ones: a simple synthesis of the methyl ether of bonducellin

In a patent application published in 1972, Baylis and Hillman reported the reaction of acetaldehyde with ethyl acrylate and acrylonitrile in the presence of catalytic amounts of 1,4-diazabicyclo[2.2.2]octane to give the α-hydroxyethylated products in good yields. No structure proof was given. The assignment eventually was shown to be correct, but since the initial disclosure was not followed by a journal publication, this remarkably simple, atom-efficient, and useful reaction was ignored for a number of years, and it has been only fairly recently that its potential has begun to be explored. The transformation is now commonly referred to as the Baylis–Hillman reaction. This is unfortunate because credit for its invention clearly belongs to Morita, who five years earlier, in patents and a brief paper reported the same reaction with the exception that tertiary phosphines were used as the catalysts; he also proposed the currently accepted mechanism. Baylis and Hillman made reference to Morita's work in their patent application. It is true that tertiary amines in general are cheaper, less toxic, and more readily removed than tertiary phosphines. However, the latter sometimes give higher yields in shorter reaction times, and there are a number of examples where they are the only useful catalysts.



The DABCO-catalyzed reaction is slow, and reaction times at room temperature of days or even weeks are common. Attempts to remedy this situation by use of other amine catalysts, change of reaction temperature, high pressure, or microwave irradiation have been partially successful. Activated olefins other than acrylonitrile and acrylic esters that have now been shown to undergo the reaction include α,β-unsaturated aldehydes and ketones, vinyl sulfoxides, vinyl sulfones, vinylsulfonates, and vinylphosphonates. β-Substituted activated olefins do not normally react. Among electrophiles other than aldehydes, unactivated ketones undergo the Morita–Baylis–Hillman reaction only under high pressure, but activation such as in α-halo ketones, α-keto esters, α-keto lactones, and nonenolizable α-diketones often produces very reactive substrates. Imines also can be employed, provided they carry a sufficiently electronegative group on nitrogen.



This chapter covers catalyzed α-hydroxyalkylations and α-aminoalkylations of activated olefins. Transition metal catalyzed reactions of this type, are also included even though they proceed by a different mechanism. Transformations that require stoichiometric amounts of reagents or more than one step are summarized in the section on Comparison With Other Methods but are not included in the Tabular Survey. The Morita–Baylis–Hillman reaction has been reviewed before.


Keywords:

catalysts;
hydroxyalklyation;
aminoalkylation;
activated olefin;
acrylates;
allenic esters;
acrylamides;
acrylonitrile;
acrolein;
unsaturated ketones;
vinyl sulfoxides;
vinyl sulfones;
vinylsulfonates;
vinylphosphonates;
substituted activated olefins;
electrophile;
intramolecular reactions;
side reactions;
aldehydes;
diketones;
keto esters;
keto lactones;
imines;
iminium salts;
Aldol and Michael reactions;
Morita-Baylis-Hillman reaction;
comparison of methods;
synthetic utility;
experimental conditions;
experimental procedures;
tabular survey

The Catalyzed α‐Hydroxyalkylation and α‐Aminoalkylation of Activated Olefins (The Morita—Baylis—Hillman Reaction)

Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2, which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (SN2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4(SN2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the SN2 reaction occurring in MeCN and the SN2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8, containing an exocyciic alkylidene and methylidene group at C(3), respectively.

Rainer Buchholz

Papers

α‐Methylidene‐ and α‐Alkylidene‐β‐lactams from Nonproteinogenic Amino Acids