Allylic substitution, Baylis-Hillman

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

Substituted allyl alcohols can be prepared on insoluble supports under mild conditions using the Baylis-Hillman reaction (Figure 7.2). In this reaction, an acrylate is treated with a nucleophilic tertiary amine (typically DABCO) or a phosphine in the presence of an aldehyde. Reversible Michael addition of the amine to the acrylate leads to an ester enolate, which then reacts with the aldehyde. The resulting allyl alcohols are valuable intermediates for the preparation of substituted carboxylic acids [43,44],... 

Intramolecular hydrogen bonding has been proposed to facilitate nucleophilic addition of sulfones to the Morita-Baylis-Hillman adducts in a single step to produce the substituted allyl sulfones.178... 

One potential problem in the reactions of stabilized allylic or propargylic carb-anions is the dimerization of the starting material if the carbanions are not formed stoichiometrically. Alkenes substituted with electron-withdrawing groups are good Michael acceptors, to which nucleophiles will undergo conjugate addition. For instance, the Baylis-Hillman reaction of allyl cyanide with benzaldehyde requires careful optimization of the reaction conditions to avoid dimerization of the nitrile (Scheme 5.12). This problem is related to a common side reaction of Michael additions reaction of the product with the Michael acceptor (Scheme 10.21). 

Furthermore, following an analogous methodology, combining the Morita-Baylis-Hillman reaction and the Trost-Tsuji reaction, Krische and co-workers have obtained allyl-substituted cyclopentenones 94 [84], Reaction was initiated by Michael addition of tributyl phosphine to an enone moiety 92, generating a latent enolate 93 which reacts intramolecularly with a jr-allylPd complex as the electrophile partner. A final -elimination step of trib-utylphosphine, favored by the presence of the methoxide ion, delivered the substituted cyclopentenones 94 (Scheme 36). 

A preparative method for allylamines is based on the Pd-catalyzed substitution reaction of /V-allylbenzotriazoles by amines. Formic acid is a convenient hydride source for allylic deoxygenation of Baylis-Hillman adducts via their derived acetates, thus the reaction is the conclusion of a three-step process for access to trisubstituted alkenes which contain one electron-deficient group. 

Chen and coworkers published a formal [3 + 3]-type reaction to give highly substituted cyclohexenes 8. This domino process consists of an allylic-allylic alkylation of an a,a-dicyanoalkene derived from 1-indanone and Morita-Baylis-Hillman carbonates, following an intramolecular Michael addition, by employing dual orga-nocatalysis of commercially available modified cinchona alkaloid (DHQD)2AQN If (hydroquinidine (anthraquinone-l,4-diyl) diether) and (S)-BINOL. The cyclic adducts... 

Allylic substitution. Alkyltitanocenes are nucleophilic toward allyUc acetates such as those derived from Baylis-Hillman adducts. Accordingly, it is applicable to the synthesis of a-alkyl-a,p-unsaturated esters. 

In their synthesis of Baylis-Hillman adducts as potential alkylating agents, Lawrence et al. attempted the oxidation of diol 56 under standard Swem conditions, with unexpected results.41 Instead of the required a-methylene-P-keto ester, the formation of an allylic chloride 57 was detected. The substitution is thought to take place via a conjugate-elimination process through enolate 59 involving the ester group, which is clearly implicated since the Swem oxidation of related alcohols such as 60 proceeds as expected. 

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. 

In numerous synthetic studies it has been demonstrated that DMP can be used for a selective oxidation of alcohols containing sensitive functional groups, such as unsaturated alcohols [297,1215-1218], carbohydrates and polyhydroxy derivatives [1216, 1219-1221], silyl ethers [1222,1223], amines and amides [1224-1227], various nucleoside derivatives [1228-1231], selenides [1232], tellurides [1233], phosphine oxides [1234], homoallylic and homopropargylic alcohols [1235], fluoroalcohols [1236-1239] and boronate esters [1240]. Several representative examples of these oxidations are shown below in Schemes 3.349-3.354. Specifically, the functionalized allylic alcohols 870, the Baylis-Hillman adducts of aryl aldehydes and alkyl acrylates, are efficiently oxidized with DMP to the corresponding a-methylene-p-keto esters 871 (Scheme 3.349) [1217]. The attempted Swern oxidation of the same adducts 870 resulted in substitution of the allylic hydroxyl group by chloride. 

A simple transition metal-free hydro/hydrothiophosphonylation of Baylis-Hillman adducts, such as substituted allyl bromides, allenylpho-sphonates and alkynes, promoted by fluoride ion in ionic liquids led to y-hydroxyphosphonates (301), a-phenyl allylphosphonate (302) and phosphonates (303-305), has been described by Swamy and co-workers. ... 

The Morita-Baylis-Hillman reaction is, in general, a carbon-carbon bondforming reaction of an a,(3-unsaturated compound with an aldehyde mediated by an organic nucleophilic base resulting in the formation of an allylic alcohol. Morita reported the use of a phosphine as catalyst and Baylis and Hillman used a tertiary amine. Variation of the electrophile to electron-deficient alkenes in a Michael-Michael elimination sequence leads to homo- and heterodimerisation and is known as the Rauhut-Currier reaction. The electrophilic aldehyde could be substituted by an imine or derivative in the aza-Morita-Baylis-Hillman reaction. Recently, there has been an increase in the use of this reaction for the construction of many different targets using many different amine derived catalysts. Scheme 2.2 shows a general view of this reaction and the accepted mechanism. ... 

Shi et al7 reported a highly enantioselective allylic substitution of Morita-Baylis-Hillman (MBH) acetate with TMSOF that could be achieved by chiral prolinamide phosphane organocatalysts 43 in good yield and high ee. 

Baylis-Hillman carbonate is a good substrate for asymmetric allylic substitution reaction, and various nucleophiles have been involved in this transformation. As shown in Scheme 9.36, the intermediate 72 (mechanistically formed by Michael... 

In 2004, Krische and colleagues demonstrated that exposure of Morita-Baylis-Hillman acetates to tertiary phosphine catalysts in the presence of 4,5-dichlorophthalimide enabled regiospecific allylic substitution through a tandem Sn2 -Sn2 mechanism. Through the use of the chiral phosphine catalyst, (i )-Cl-MeO-BIPHEP, the racemic Morita-Baylis-Hillman acetate depicted in Scheme 2.108 was converted into the corresponding enantiomerically enriched allylic amination product, thus establishing the feasibility of DKR. 

In the course of developing an easy access to chiral y-butenolides, Shi et al. have established an efficient multifunctional chiral binaphthyl phosphine-catalysed allylic substitution of Morita-Baylis-Hillman acetate with 2-tri-methylsiloxy furan. The regjospecific allylic substitution occurred to provide the xyra-y-butenolide in good to excellent yield, high regjoselectivity and excellent enantioselectivity by using water as an additive. The scope of this reaction could be successfully extended to a variety of Morita Baylis Hillman acetates, as shown in Scheme 5.10. 

Recently, 4 was reported to be an excellent catalyst for the enantioselective substitution of Morita-Baylis-Hillman carbonates with allylamines [21]. Only carbonates with an aromatic group gave the desired enantioenriched N-allyl-P-amino-methylene esters (Scheme 6.6). Ring-closing metathesis of the products of the allylation reaction was shown to result in chiral 2,5-dihydropyroles of importance as starting materials for the synthesis of products of biological and medical interest. 

Zhang, T.-Z., Dai, L.-X., and Hou, X.-L. (2007) Enantioselective allylic substitution of Morita-Baylis-Hillman adducts catalyzed by planar chiral [2.2] paracyclophane monophosphines. Tetrahedron Asymmetry, 18,1990-1994. 

A rapid S allylic substitution of Baylis-Hillman acetates with ethyl(triphenyl phosphoranylidene) acetate was reported by Yadav et al. (2007) to give ethyl-5-aryl or alkyl-(E)-pent-4-enoates with high (E)-stereoselectivity under microwave irradiation. 

This chapter reviews our study of Morita-Baylis-Hillman (MBH) and vinylmel ation reactions for the synthesis of achiral and chiral, functionalized, fluorinated allyl alcohols. Vinylmetalation of fluoro-carbonyls with aluminum and copper reajgents for the synthesis of unsubstituted, and p-substituted fluorinated allyl alcohols is summarized. An exploratory study of terpenyl alcohols as chiral auxiliaries in these reactions is also discussed. 

The asymmetric allylic substitution reaction of Morita-Baylis-Hillman carbonates (226) with diphenyl phosphite in the presence of chiral multifunctional thiourea-phosphine catalyst (228) provided allylic phosphites (227) in high yields and with excellent enantioselectivities (Scheme 76). 

Synthesis of a series of novel functionalized achiral and chiral allyl boronates has been recently reported by Ramachandran via nucleophilic SNj -type addition of copper boronate species (generated from the boronates 37, 141, 142 under Miyaura conditions) [115,116] to various functionalized allyl acetates that tvere prepared either via vinylalumination or by Baylis-Hillman reaction with various aldehydes [117]. The resulting allylic boronates bearing an ester moiety (X=OR) were subsequently used for the synthesis of a-alkylidene-/3-substituted-y-butyrolactones by allylboration of aldehydes (Scheme 3.76). 

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