Recent Advances in the Baylis−Hillman Reaction and Applications

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

2. Essential Components: Earlier Developments 5449 2.1. Activated alkenes/alkynes 5450 2.1.1. Acyclic activated alkenes/ alkynes 5450 2.1.2. Cyclic activated alkenes 5451 2.2. Electrophiles 5451 2.3. Catalysts 5452 3. Essential Components: Recent Developments 5452 3.1. Activated Alkenes/Alkynes 5452 3.2. Electrophiles 5460 3.3. Catalysts 5477 4. Asymmetric Baylis-Hillman Reaction: Earlier Developments 5495

Recent contributions from the Baylis-Hillman reaction to organic chemistry.

The hetero Diels-Alder reaction is one of the most important methods for the synthesis of heterocycles. In this article an overview is given for the period since 1989 describing the reaction of heterobutadienes such as oxabutadienes, thiabutadienes, azabutadienes, diaazabutadienes, nitroso-alkenes and nitroalkenes as well as of heterodienophiles such as carbonyls, thiocarbonyls, imines, iminium salts, azo- and nitroso compounds. In addition, several other less common hetero Diels-Alder reactions such as cycloadditions of thiaazabutadienes, oxaazabutadienes, dioxabutadienes, dithiabutadienes, oxathiabutadienes, diazaoxabutadienes as well as the use of N-sulfinyl-phosphaalkynes and other dienophiles are mentioned. A main point of discussion is the stereoselectivity of the reactions and the preparation of enantiopure compounds either using dienes and dienophiles carrying a chiral auxiliary or employing chiral Lewis acids. A point stressed is the synthesis of natural products using hetero Diels-Alder reactions leading to carbohydrates, alkaloids, terpenes, antibiotics, mycotoxins, cytochalasans, antitumor agents and several other classes of natural products.

Hetero diels-alder reactions in organic chemistry

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)

The title class of 1,1-diactivated ethylenes has been prepared in two steps from aldehydes and t-butyl acrylate by (i) DABCO-catalyzed coupling to give t-butyl 2-(hydroxyalkyl)-2-propenoates 11 and (ii) low-temperature Jones oxidation, followed by swift work up at low temperature. The resulting t-butyl 2-methylene-3-oxoalkanoates 12 are stabilized by sterically demanding and also by aromatic groups R. For primary unhindered alkyl groups, stability is low. The compounds enter into Michael reactions, hetero Diels-Alder additions with enol ethers, and self-dimerization.

Preparation and Selected Reactions of t‐Butyl 2‐Methylene‐3‐oxoalkanoates

A variety of 9,10–dihydro–9,10–propanoanthracen–12–ones 1–11 has been prepared from anthracenes 15–23, α,α′-dibromo ketones 12–14 and zinc/copper couple by using dioxane as solvent and ultrasonication at 15–20°C. 2,2,4,4–Tetrabromoacetone (12) afforded cycloadducts, in which the two bromine atoms at C–11 and C–13 are introduced stereoselectively cis and adopt a syndiaxial instead of a cis-diequatorial position (5 examples). Even the cis-configurated methyl groups in adducts 8, 9 and cis-11 adopt syndiaxial positions preferentially.

Synthesis of 9,10–Dihydro–9,10–propanoanthracen–12–ones Substituted at the Bridgehead

Sonication of a zinc/copper couple, N,O-bis(trimethylsilyl)-acetamide (BSA) and α,α'-oligobromo ketones in benzene gives rise to oxyallyl intermediates which cycloadd to anthracene. Starting from 1,1,3,3-tetrabromoacetone (2a) and anthracene (1a), we obtained 11,11,13-tribrominated adduct 4 as the major product (42%). The expected 11,13-dibrominated adduct trans-3 was formed as a minor product (5%), but it became the main product when the known oxyallyl methodology was applied. Dibenzohomobarrelenes 9 and 17 were prepared by short routes.

Synthesis of 9,10‐Dihydro‐9,10‐propanoanthracene‐12‐ones from Anthracenes and Oxyallyl Cation Intermediates Generated by the the BSA [N,O‐Bis(trimethylsilyl)acetamide] Method

Synthesis of homobenzoctamine [9,10-dihydro-9-(1-methylaminomethyl)-9,10-propanoanthracene] and homomaprotiline [9,10-dihydro-9-(3-methylaminopropyl)-9,10-propanoanthracene]

H. Martin

Papers

Preparation and Selected Reactions of t‐Butyl 2‐Methylene‐3‐oxoalkanoates

Synthesis of 9,10–Dihydro–9,10–propanoanthracen–12–ones Substituted at the Bridgehead

Synthesis of 9,10‐Dihydro‐9,10‐propanoanthracene‐12‐ones from Anthracenes and Oxyallyl Cation Intermediates Generated by the the BSA [N,O‐Bis(trimethylsilyl)acetamide] Method

Synthesis of homobenzoctamine [9,10-dihydro-9-(1-methylaminomethyl)-9,10-propanoanthracene] and homomaprotiline [9,10-dihydro-9-(3-methylaminopropyl)-9,10-propanoanthracene]