Baylis-Hillman-type reactions

Scheme 4.57 Chiral allenes by an asymmetric Baylis—Hillman type reaction.

A highly enantioselective proline-catalysed intramolecular Morita-Baylis-Hillman reaction of hept-2-enedial (111) has been reported. Addition of imidazole to the mixture resulted in an unusual inversion of enantioselectivity.149 The first example of a TiCU-mediated Morita-Baylis-Hillman-type reaction of cy-acetyl cyclic ketene dithioacetals with arylaldehydes has been described.150... 

Sanhao et al. have proposed to utilise a Baylis-Hillman type reaction between dialdehydes and diacrylates to obtain polymers with a polyester backbone and alcohol and double bond side-groups [87]. The authors reported this material to be a very interesting intermediate towards side-chain modified polymers. 

Contra-Peterson elimination also occurred in Morita-Baylis-Hillman-type reactions of 1-silylcyclopropene 101. Addition of the nucleophilic catalyst tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP) at the 2-position of the alkene and condensation of the anion with an aldehyde led to 1,3-Brook rearrangement, with expulsion of the catalyst to regenerate the cyclopropene double bond in product 102. ... 

Under high pressure (10 kbar), the p-hydride elimination is retarded and the metastable a-alkylpalladium halide may insert into the double bond of a second acrylate to eventually— after double shift— yield a diethyl (arylmethylene)glutarate (Scheme 5-33). Alternatively, the acrylate may dimerize first e.g., via a Baylis-Hillman-type reaction), and the diethyl 2-methyleneglutarate subsequently undergo a Heck arylation. 

Cihalova S, Remes M, Cisarova I, Vesely J. Highly enantioselective aza-Baylis-Hillman-Type reaction of a,(3-unsaturated aldehydes with in situ generated A-Boc and A-Cbz-imines. Eur. J. Org. Chem. 2009 (36) 6277-6280. 

PTA was used as an organic base to catalyze Morita-Baylis-Hillman type reactions (Scheme 7.9) [49-51]. Variously substimted aryl aldehydes ArCHO were reacted with ethyl acrylate in THF/H2O (4 1, v/v) at room temperature in the presence of a catalytic amount of 1 (20 mol %) giving the addition products after 5-19 h in yields ranging from 59 to 93%. 

A new method has been developed for the synthesis of ( )-3-methyl Baylis-Hillman-type adducts with high E/Z (>93%) selectivity in modest to good yields. The process consists of two steps an indium-mediated allylation reaction and a simple base-catalyzed isomerization step (Eq. 8.61). Various aldehydes were allylated with allyl bromides using indium under very mild conditions in aqueous media and thus converted to the Baylis-Hillman-type adducts.150... 

A Baylis-Hillman type product has been obtained through a ring-opening reaction of an epoxide with an allenoate <06OL2771>. The reaction of MgL, with ethyl propiolate provides the iodo allenoate 32. This nucleophile reacts with an aryl epoxide to provide the homoallylic alcohol 33. The Z iodide is the major product formed. 

The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true Morita-Baylis-Hillman reaction of an epoxide has recently been reported <06CC2977>. Treatment of enone 34 with Me3P provides a good yield of the epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. 

A titanium(iv) chloride mediated Baylis-Hillman-type or aldol reaction between a-ketoesters and cyclohex-2-enones has been studied (Equation (13)).77 The steric effect of the R2 substituent is crucial for the reaction pathway since the aldol reaction only proceeds with the unsubstituted cyclohexenone (aldol adduct 71 with R2 = H to a small extent the Baylis-Hillman reaction occurs), whereas with the substituted substrate (R2 = Me) gives exclusively the Baylis-Hillman adduct 72. 

It is also possible to carry out a substrate-controlled reaction with aldehydes in an asymmetric way by starting with an acetylene bearing an optically active ester group, as shown in Eq. 9.8 [22]. The titanium—acetylene complexes derived from silyl propiolates having a camphor-derived auxiliary react with aldehydes with excellent diastereoselectivity. The reaction thus offers a convenient entry to optically active Baylis—Hillman-type allyl alcohols bearing a substituent (3 to the acrylate group, which have hitherto proved difficult to prepare by the Baylis—Hillman reaction itself. 

Sato and coworkers have reported an asymmetric synthesis of Baylis-Hillman-type allylic alcohols 48, 49 via a chiral acetylenic ester titanium alkoxide complex (Scheme 9) [41]. These reactions rely on the use of the novel acetylenic ester titanium alkoxide complex 44 with a camphor-derived chiral auxiliary. Optically active, stereodefined hydroxy acrylates 46, 47 were obtained in high yields and with excellent regio- and diastereoselectivities. The chiral auxiliary was subsequently cleaved off by alcoholysis. 

The asymmetric catalytic aldol reaction of silyl allenolates ICH=C=CR2OSiMe3 with aldehydes R CHO has been achieved by Li et al. by using N-C3F7CO oxazaborolidine as the catalyst [43], The fluoroacyl group of the catalyst was found to be crucial for control of enantioselectivity. The reaction provides the first enantioselective approach to / -halo Baylis-Hillman-type adducts. 

Hydroxybenzaldehydes react with alkyl vinyl ketones in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) to yield 3-acyl-277-chromenes (Scheme 19) <2000J(P 1)1331 >. The reaction proceeds via a Baylis-Hillman type pathway to form the zwitterionic intermediate 61 with subsequent cyclization and dehydration to afford 2-acyl-2H-chromenes (Scheme 19) <20030BC1133>. 

Of the numerous examples of asymmetric reactions catalyzed by Lewis bases, this chapter focuses mainly on the activation of silicon reagents and related processes. Various other types of Lewis basic (nucleophilic) activation, namely the Morita-Baylis-Hillman (MBH) reaction, acyl transfer, nucleophilic carbenes, and carbonyl reduction, are described in the other chapters of this book. 

A review on ynolates, including the synthesis of p-lactones, has appeared <03S2275>. Morita-Baylis-Hillman-type adducts have been converted into a-alkylidene-p-lactones 65, which on reaction with dimethyltitanocene can be transformed into 3-alkylidene-2-methyleneoxetanes <03OL399>. Lactones 66 have been obtained via the cinchona alkaloid-catalyzed dimerization of monosubstituted ketenes <03OL4745>. The PdCh-promoted synthesis of P-lactones 67 have been achieved via cyclocarbonylation of 2-alkynols <03OL4429>. 

The Wang group also realized enantioselective oxidative cross-coupling reactions between tertiary amines and the activated olefins by merging Cu(OTf)2 with quinine as the best cooperative catalysts/ A Morita-Baylis-Hillman-type mechanism is in operation. It was notable that molecular oxygen was employed as the sole oxidant. As shown in Scheme 2.12, the reactions between Ai-aryl THIQs and the a,p-unsaturated aldehydes or ketones 30 proceeded smoothly to afford the a-functionalized products 31 in up to 81% yield and 99% ee. 

Another class of reaction for which chiral tertiary amines are privileged catalysts is the Morita-Baylis-Hillman type (477, 478). One of the first applications of Cinchona alkaloids to mediate an asymmetric Morita-Baylis-Hillman reaction in a natural product synthesis was reported by Hatakeyama et al. in 2001 (479). Using a stoichiometric amount of (3-isocupreidine (568), a stereoselective addition of hexafluoroisopropyl acrylate (569) to aldehyde 570 could be carried out in good yield and with excellent selectivity (99% ee) (Scheme 119). The chiral p-hydroxy ester 571 was converted further into the epoxide 572, a known intermediate in the synthesis of epopromycin B (573). Epopromycin B (573) is a plant cell wall... 

A general, one-pot synthesis of substituted tetraethyl 2-aminoethylidene-1,1-bisphosphonates (133) has been developed by Gajda. The direct and efficient conversion of the latter into aza-Moritae-Baylis-Hillman-type adducts (134), via the Horner-Wittig reaction with paraformaldehyde, has been also elaborated (Scheme 44). 

Shibasaki et al. also reported that similar Morita-Baylis-Hillman-type products were obtained via asymmetric aldol reaction of a p,y-unsaturated ester with aldehydes using a chiral barium catalyst system (Table 3) [25]. The desired products formed in good yields with high enantioselectivities after isomerization. Several aromatic- and alphatic aldehydes were tested, and in all cases high a-(E) selectivities and high enantioselectivities were observed. Several aryl, heteroaryl, alkenyl, and alkyl aldehydes can be used as substrates in this reaction. 

Shibasaki et al. also developed chiral barium catalysts prepared from barium alkoxide and optically active BINOL 3 or aryloxide 4 derivatives. These catalysts were applied to asymmetric Mannich reactions of p,y-unsaturated esters (Table 27) [101]. In this reaction, the initially formed Mannich adducts isomerized to afford aza-Morita-Baylis-Hillman-type products in moderate to good yields with good enantioselectivities. For four substrate examples, ayloxide 4 ligand worked well (entries 2—4). 

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. 

Moreover, a twofold SN -type domino reaction was reported by Krische and coworkers for the synthesis of y-butenolides 2-229 (Scheme 2.53) [128]. Treatment of Morita-Baylis-Hillman acetates 2-226 with trimethylsilyloxyfuran (2-227) in the presence of triphenylphosphane in THF at 0 °C led to 2-229 in yields of up to 94% and diastereoselectivities of >95 5. 

Chiral fe-thiourea-type catalysts effectively provide the Baylis Hillman reaction with cyclohexenone and aldehydes.181 In several reactions, thiourea derivatives have been used as significant and specific catalyst because of their intermolecular hydrogen bonding ability (Scheme 74).182 186... 

When methylene bisphosphonate (169) is reacted in a Horner reaction with an aromatic aldehyde, the alkenyl phosphonate 170 is produced (Scheme 5.25). By metalation with LDA in THF, this is converted to the vinyllithium intermediate 171 that, with the ketone 172, affords a Baylis-Hillman reaction-type product, 173 on base treatment, this is converted to the arylallene 174 [67]. 

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