Baylis-Hillman product

When aryl acrylates and phenyl salicylates react with aliphatic aldehydes in the presence of DABCO, the normal Baylis-Hillman product (39) often reacts further to give the acetal (40) <96TL1715,96TL3755>. 

The reduction of aromatic nitro compounds to amino derivatives and cyclizations to various heterocyclic compounds are presented in Chapter 9. Recent advances are presented here. Reaction of 2-nitrobenzaldehyde with vinyl carbonyl compounds in the presence of 1,4-diazbi-cyclo[2.2.2]octane affords Baylis-Hillman products, the catalytic reduction of which results in direct cyclization to quinoline derivatives (Eq. 10.78).134... 

When the R group in the Baylis-Hillman products is not H, a problem might arise in the allylic ring-closing etherification (direct vs allylic attack of the phenolate), leading to mixtures of regio-isomers. Therefore, in an initial study we used parent acid 88 to avoid these problems (Scheme 15). 

Studies on catalytic asymmetric aza-Baylis-Hillman reaction has shown that the reaction involves rate-limiting proton transfer in the absence of added protic species, but exhibits no autocatalysis.41 Brpnsted acidic additives lead to substantial rate enhancements through acceleration of the elimination step. Furthermore, it has been found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the aza-Baylis-Hillman product by proton exchange at the stereogenic centre. 

During the course of the Baylis-Hillman-reaction two stereocenters are formed, one of which remains in the Baylis-Hillman-product. An obvious concept for the development of an asymmetric version of the reaction represents the use of an enantiomerically pure acrylic acid derivative. The use of enantiomerically pure menthyl acrylates resulted, but only in certain cases, to respectable diastereomeric excesses [21]. A significant improvement was reported in 1997 by Leahy and coworkers who used the Oppolzer-sultame as a chiral auxiliary in DABCO-catalyzed Baylis-Hillman-reactions (Scheme 2) [22]. In this reaction, the... 

Very good enantioselectivities were recently reported by Hatakeyama and coworkers [33]. The reaction of a variety of aldehydes 28 with the highly reactive 1,1,1,3,3,3-hexafluoro iso-propylacrylate 27 using modified Cinchona-alkaloids as the catalyst resulted, at a temperature of-55 °C, in formation of the Baylis-Hillman-products 30 in 31-58% yields with 91-99% ee (Scheme 6). The use of the tricyclic derivative 29, which was prepared from quinidine in one step [34], proved crucial in order to obtain high enantioselectivities. The success of catalyst 29 can be explained by the (compared with quinidine) increased nucleophilicity, by the... 

The conjugate addition of (K)-N-methyl-N-a-methylbenzyl amide 33 to tert-butyl cinnamate 34, followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination afforded the -substituted homochiral Baylis-Hillman product 39 in good yield (Scheme 7) [37]. This chemistry requires the use of stoichiometric rather than catalytic amounts of the chiral base. 

A number of alternative syntheses of non-racemic Baylis-Hillman-products by other methods have been reported. Barrett and coworkers developed a two-step synthesis of a-methylene-/ -hydroxyketones 43 with 34-94% ee (Scheme 8) [39]. From a preparative view-... 

Syntheses of Non-Racemic Baylis-Hillman-Products by Other Methods 1173... 

An alternative ring construction approach to 1,4-oxazepin-7-ones (e.g. 241) utilises the Baylis-Hillman product 240, subsequent reaction with a p-aminoalcohol, and ester hydrolysis followed by DCC-mediated intramolecular coupling to afford 241. This sequence can be generalised to give a range of analogues [02S2232],... 

The reaction can be modihed to give additional products, as with the reaction of o-hydroxybenzaldehyde and methyl vinyl ketone with DABCO, where the initial Baylis-Hillman product cyclized via conjugate addition of the phenolic oxygen to the conjugated ketone (15-31). ° Aldehydes and conjugated esters can be coupled with a sulfonamide to give an allylic amine. 

It was shown in the laboratory of P.T. Kaye that the reactions of 2-hydroxybenzaldehydes and 2-hydroxy-1-naphthaldehydes with various activated aikenes proceeded with regioseiective cyclization under Baylis-Hillman conditions to afford the corresponding 3-substituted 2H-chromene derivatives in high yields. Previous attempts to prepare 2H-chromenes chemoselectively via the cyclization of 2-hydroxybenzaldehyde-derived Baylis-Hillman products had proven unsuccessful. Complex mixtures containing coumarin and chromene derivatives were obtained. Good results were observed after the careful and systematic study of the various reactants and reaction conditions. 

Lawrence, N. J., Crump, J. P., McGown, A. T., Hadfield, J. A. Reaction of Baylis-Hillman products with Swem and Dess-Martin oxidants. 

Allylic chlorides. A facile s Baylis-Hillman products involves re 1,2,3-Trienes. A formal I... 

AllyUc chlorides A facile synthesis of (Z)-2-chloromethylcinnamic esters from Baylis-Hillman products involves reaction with MsCl-EtjN. 

One arm of the imidazolium scaffold contains the catalytic centre, a bridgehead nitrogen atom that possesses the required nucleophilicity, and the second arm contains a primary alcohol capable of speeding up the critical proton transfer step that leads to the P-ammonium enolate intermediate, the direct precursor of the final Baylis-Hillman product. The reaction of aliphatic and aromatic aldehydes with acrylates is carried out under solvent free conditions at room temperature, affording 80-95% yields of adducts after 8-12 h at rt. Moreover, catalyst 34 can be readily recovered from the reaction mixture and reused at least six times without significant loss of catalytic activity. 

All the reactions reported on here used 1 mmol NBA, 2 mmol MA and 1 mmol of DABCO. When the reaction was performed neat a 94% yield of the Baylis-Hillman product (BHP) was obtained after 2 hours at 20°C. When the reaction was carried out in 20 mL toluene at 20 C for 24 hours, no product was... 

Pro-azaphosphatranes lb or Id catalyze the reaction of activated allylic compounds with aromatic aldehydes to produce either a Baylis-Hillman product or a j8,y-unsaturated 1,2-addition product, depending on the type of allylic compound employed [131]. As seen in Eqs. (18) and (19), the activated allylic compounds shown react efficiently with aromatic aldehydes in the presence of 20 to 40 mole percent of lb or Id to give exclusively a-addition products. Such products are useful intermediates for the synthesis of substituted tetrahydrofurans through base-promoted electrophilic cyclizations. To our knowledge there have been only a few reports in which allylic cyanides and esters of the type used here have been utilized in 1,2-addition to aldehydes [131]. In those reports, an ionic base was used, y addition was observed, or a mixture of a- and y-addition products were obtained. The latter two observations contrast ours in which exclusive a-addition occurred. 

Allyl cyanide on the other hand, Eq. (20), results in an allylic transposition affording only the Baylis-Hillman product. The Baylis-Hillman reaction has long been of interest. Generally, high pressure is required to induce such a reaction and an amine such as DABCO as well as lengthy reaction times (1-4 weeks) are usually required [131]. The transformation shown in Eq. (20) advantageously affords this product under very mild conditions and in very short reaction times compared with both older as well as more recent literature approaches. Furthermore, this reaction is successful with aromatic aldehydes that have generally led to unreliable results under typical Baylis-Hillman conditions. 

Substituted glutaric acids [29] were obtained from the ethyl malonic acid ester of the Baylis-Hillman product 14. The enolate of this ester, generated with LDA at -78 °C rearranged to give the substituted glutaric acids in good yield (Scheme 5.1.18). 

On the other hand, the Morita Baylis Hillman reaction has been investigated in the presence of various chiral thioureas as organoeatalysts. In parti-eular, a chiral bis-thiourea prepared from trani-l,2-diaminocyclohexane was found to promote, in the presence of DMAP, the Morita-Baylis-Hillman reaction of cyclic enones with a wide range of aldehydes. Indeed, aromatic as well as aliphatic aldehydes led to the corresponding Morita-Baylis-Hillman products in moderate to excellent yields and ee values reached up to 90% ee, as summarised in Scheme 2.56. 

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