Intramolecular Baylis-Hillman reaction

An intramolecular variant of the Baylis-Hillman reaction is also possible, and may be used for the construction of functionalized ring systems, e.g. a cyclopen-tene derivative such as 12. However, good yields have been achieved in only a few cases ... 

Intramolecular versions of the Morita-Baylis-Hillman reaction have also met with success using a dual Lewis acid/Lewis base catalyst system. Miller has shown that a combination of A-methyl imidazole (132) (10 mol%) and... 

Scheme 53 Intramolecular Moiita-Baylis-Hillman reaction...

An interesting alternative intramolecular cyclisation was discovered by Jprgensen and co-workers [187]. Although not strictly exploiting an enamine intermediate, the transformation represents a secondary amine catalysed Morita-Baylis-Hillman reaction leading to a series of highly functionalised cyclohexene products. Reaction of the Nazarov reagent 137 with a,P-unsaturated aldehydes in the presence of the diarylprolinol ether 30 led to the cyclohexene products 138 (49-68% yield 86-96% ee) via a tandem Michael/Morita-Baylis-Hillman reaction (Scheme 54). 

A study of the effect of the Michael acceptor configuration on the efficiency of intramolecular Morita-Baylis-Hillman reactions has been performed. Enones containing a pendant aldehyde moiety attached at the -position of the alkene group were employed as substrates and the reactions were catalysed by a phosphine. In all cases examined, with Ph3P as the catalyst, cyclization of (Z)-alkene (117) gave 2.5-8.5 times higher yield than with the E-isomer (115) under identical reaction conditions, both affording the same product (116). Steric effects are believed to be the source of this difference in reactivity.172... 

An intramolecular vinylogous Morita-Baylis-Hillman reaction, followed by intramolecular aldol cyclization,129 is described under Intramolecular Aldols above. 

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). 

Baylis-Hillman Reaction. Intramolecular cyclization of MeC0(CH2)2CH=CHC02Et using (-P)-CAMP produced the cy-clopentene in 40% isolated yield. A 3 1 equilibrium mixture which favored the product cyclopentene was formed after 10 days at 25 °C. CAMP was found to be superior to other phosphines, such as PBU3. DABCO and other nitrogen bases were ineffective for the cyclization reaction. However, the enantioselectivity of the product using CAMP was only 14%. 

Mergott, D. J., Frank, S. A., Roush, W. R. Application of the Intramolecular Vinylogous Morita-Baylis-Hillman Reaction toward the Synthesis of the Spinosyn ATricyclic Nucleus. Org. Lett. 2002, 4, 3157-3160. 

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. 

Mergott, D.J., Frank, S.A., and Roush, W.R., Application of the intramolecular vinylogous Morita-Baylis-Hillman reaction toward the synthesis of the spinosyn A tricyclic nucleus, Org. Lett., 4, 3157, 2002. 

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>. 

In a reversal of this intramolecularized side-chain reactivity (effecting annulation of a five-membered ring to the N/C-2-position of pyridine) the Baylis-Hillman reaction of pyridine-2-aldehydes with acceptor-substituted alkenes, e.g. acrylates, in the presence of DABCO gives rise to formation of products 74, which can be cyclized to 2-substituted indolizines, e.g. indolizine-2-carboxylates 75 [54]. 

There have been only a few reports on asymmetric versions of the intramolecular MBH reaction Scheme 1.105 shows one representative example. The intramolecular Morita Baylis Hillman reaction has been achieved with unprecedented levels of enantioselectivity by using a co-catalyst system involving pipecolinic acid and iV-methylimidazole cyclic MBH products 289 were... 

The L-threonine-derived phosphine-sulfonamide (23) is one of the best catalysts for the enantioselective aza-Morita-Baylis-Hillman reaction. A DPT study has identified ( ) a key intramolecular N-H—O hydrogen-bonding interaction between the sulfonamide... 

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