Intramolecular, addition Baylis-Hillman 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... 

The rate and the conversion of the Baylis-Hillman-reaction was significantly improved when nucleophilic non-hindered bases, such as diaza[2.2.2]bicyclooctane (DABCO, 6), rather than simple tertiary amines were used. Further improvements were observed when 3-quinuclidinole (3-QDL, 7) was employed, due to stabilization of the zwitterionic intermediate 2 by formation of intramolecular hydrogen bonds [14a-c]. Similar effects were observed by the addition of methanol [14d] or acetic acid [14e] to the reaction mixture (formation of intermolecular hydrogen bonds) or by the presence of a hydroxy group in the acrylate [14f ]. The rate of the reaction was decreased by the presence of substituents in the a-position of tertiary amines. This was explained by the decrease of the rate of the addition of the catalyst onto the acrylate [15]. 

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

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). 

Heck reaction. An intramolecular version is exploited in closing the five-membered ring to complete the tetracyclic system of mappicine. A new synthesis of P-ketoesters is via the Heck reaction of aryl halides with the Baylis-Hillman reaction products. Additives have important influences on the products derived from aryl halides and 2,3-dihydrofuran ... 

The Baylis-Hillman reaction has become a very powerful carbon-carbon bond forming reaction in the past 20 years. A typical reaction involves an activated olefin (i.e., an acrylate) and an aldehyde in the presence of a tertiary amine such as diazobicyclo-[2.2.2]octane (DABCO) to form an a-meihylhydroxyacrylale. A host of activated olefins have been utilized including acrylates, acroleins, a, 3-unsaturated ketones, vinylsulfones, vinylphosphonates, vinyl nitriles, etc. The Baylis-Hillman has been successfully applied inter- and intramolecularly. In addition, there are numerous examples of asymmetric Baylis-Hilhnan reactions. Reviews (a) Ciganek, E. Org. React. 1997, 51, 201-478. (b) Basavaiah, D. Rao, P. D. Hyma, R. S. Tetrahedron 1996, 52, 8001-8062. (c) Fort, Y. Berthe, M. C. Caubere, P. Tetrahedron 1992, 48, 6371-6384. 

The Baylis-Hillman reaction of pyran-4-ones and chromones with aldehydes is efficiently catalysed by NaOMe or DBU <04JOC8413> and when applied to salicylaldehyde and cyclohexenone a tetrahydroxanthen-l-one results possibly via a domino Michael addition and intramolecular aldol condensation <04AG(E)115>. 

Baylis-Hillman adducts such as 55 and 56 derived from 2-nitrobenzaldehydes were shown to function as useful precursors to functionalized (1H)-quinol-2-ones and quinolines. Treatment of 55 and 56 with iron and acetic acid at 110 °C afforded 57 and 58, respectively <02T3693>. A variety of other cyclization reactions utilized in the preparation of the quinoline scaffold were also reported. An iridium-catalyzed oxidative cyclization of 3-(2-aminophenyl)propanols afforded 1,2,3,4-tetrahydroquinolines <02OL2691>. The intramolecular cyclization of aryl radicals to prepare pyrrolo[3,2-c]quinolines was studied <02T1453>. Additionally, photocyclization reactions of /rans-o-aminocinnamoyl derivatives were reported to provide 2-quinolones and quinolines <02JHC61>. Enolizable quinone and mono- and diimide intermediates were shown to provide quinolines via a thermal 6jt-electrocyclization <02OL4265>. Quinoline derivatives were also prepared from nitrogen-tethered 2-methoxyphenols. The corresponding 2-methoxyphenols were subjected to a iodine(III)-mediated acetoxylation which was followed by an intramolecular Michael addition to afford the quinoline OAc O... 

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... 

A related approach for the synthesis of spirocyclopenteneoxindoles was developed by Barbas and coworkers. Chiral diphosphines catalyzed the [3+2] cycloaddition between the A-protected methyleneindolin-2-ones 17b and the Morita-Baylis-Hillman (MBH) carbonates 37 [18]. This reaction was initiated by the displacement of the carbonate moiety by the phosphine VI, an addition-elimination mechanism, which was followed by the deprotonation to afford ylide 39. A regioselective nucleophilic addition on 17 by 39, followed by an intramolecular conjugate addition, afforded intermediate 40 that, after elimination of PR3, delivered the corresponding spirocycle 41 (Scheme 10.11). 

The introduction of the activated allylic bromides and Morita-Baylis-Hillman acetates and carbonates pioneered the development of a number of phosphine-catalyzed reactions in subsequent years [45]. Interestingly, the asymmetric variant of this type of transformation only appeared in the literature seven years later. In 2010, Tang, Zhou, and coworkers disclosed a highly enantioselective intramolecular ylide [3-f2] annulation using spirobiindane-based phosphine catalyst 31 (Scheme 20.27). BINAP was found inactive in this reaction even at an elevated temperature (70°C). Notably, both optically active benzobicyclo[4.3.0] compounds 32 and 32 with three continuous stereogenic centers could be obtained as major products in high yields and stereoselectivities just by a choice of an additive [Ti(OPr )4], which can block the isomerization of the double bond [46]. 

The t/z/a-Michael addition followed by an intramolecular cyclisation were used as key reactions in an efficient, one-pot, diastereoseletive synthesis of 3-nitrothietanes (82) and (83). Thus, Baylis-Hillman alcohols (79) and the coresponding aldehydes (80) were reacted with diethyl phosphorodithioate (81) itself or in a combination with a task-specific ionic liquid to afford the corresponding 2,3-di- and 2,3,4-trisubstituted thietanes, (82) and (83), with complete diastereoselectivity in favour of the tram isomers (Scheme 27). ... 

---