Baylis-Hillman cyclization

Roush and coworkers developed a new one-pot sequence consisting of an intramolecular Diels-Alder- and an intramolecular vinylogous Morita-Baylis-Hillman-cyclization for the synthesis of spinosyns [31]. These compounds are poly-ketide natural products possessing extraordinary insecticidal activity. 

The key tricyclic intermediate toward the total synthesis of spinosyn A was assembled by W.R. Roush et al. featuring a one-pot tandem intramolecular Diels-Alder reaction and an intramolecular vinylogous Baylis-Hillman cyclization. The cyclization precursor was prepared via the S-G modified HWE reaction. 

Methot, J. L., Roush, W. R. Synthetic Studies toward FR182877. Remarkable Solvent Effect in the Vinylogous Morita-Baylis-Hillman Cyclization. Org. Lett. 2003, 5,4223-4226. 

Scheme 4.27 Intramolecular Morita-Baylis-Hillman cyclization in the synthesis of...

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... 

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. 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

The combination of Baylis-Hillman reaction and tandem radical addition/ cyclization sequences [259], has been reported as a useful synthetic tool for the asymmetric synthesis of functionalized monocyclic and bicyclic (3-lactams (III and IV, Fig. 7). 

Tri- and tetrasubstituted oxepanes 47 can be obtained in 50-60% overall yield (Scheme 15) using vinyl radical cyclization of homopropargyl and arylhomopropargyl derivatives 48 of Baylis-Hillman adducts 49, followed by methylidene group deprotection using pyridinium/>-toluenesulfonate (PPTS) <2005TL3369>. 

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. 

Remarkably, thermolysis of the Baylis-Hillman adducts 311 (R1 = alkyl or aryl Rz = Ac, CN, CC Me) in toluene at 210 °C in a sealed tube gave stereoselectively the cyclized product (+)-312, which included incorporation of the elements of the solvent and, when Rz = Ac, a single isomer was obtained (Equation 33). The yields were moderate (37-56%) and when RZ = CN and C02Me some racemization occurred. Similar results were obtained when either p-xylene or mesitylene was used but no reaction occurred when chlorobenzene or anisole was used. Unsaturated rings are obtained in similar yields and stereoselectivity if the N-substituent is an alkyne. In addition, benzene thiol reacted in boiling benzene in the presence of AIBN to give 313, which on ozonolysis yielded the cyclic ketones 314 ( = 1-3) in 52-70% yield <2001JOC1612>. 

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>. 

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... 

A new route to 6-substituted pyrrolo[2,l-b]thiazoles 58 takes advantage of an intramolecular thermal cyclization of acetates 56 <07S3037>. These acetates are easily derived from the Morita-Baylis-Hillman adducts of thiazole-2-carboxaldehyde. This strategy has also been extended to the synthesis of the tricyclic analogs 60. 

Baylis-Hillman acetates have been conveniently transformed into tri/tetracyclic heterocyclic frameworks containing an azocine moiety via a one-pot multistep protocol involving alkylation, reduction, and cyclization sequence <2007OL2453>. Treatment of Baylis-Hillman acetate 284 with 1,3-cyclohexanedione in the presence of K2CC>3, followed by treatment of the resulting product with Fe/AcOH, gave 77% fused azocine 285 (Scheme 119). 

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%. 

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. 

Solid-phase synthesis by the cyclization of polymer-bound hydrazones of [1-keto esters. Jung and co-workers (99JOC1362) (Scheme 24) have reported the synthesis of pyrazol-3-one 102 from polymer-bound /1-keto ester 100 and phenyl hydrazine. In the first step, polymer-bound 3-hydroxy-2-methylidenepropionic acid 99 is derived from a Baylis-Hillman reaction between polymer-bound allylic alcohol... 

Barbier reactions. Allylic alcohols are produced from alkenyl halides and carbonyl compounds on mediation by Sml2. This process includes the preparation of the Baylis-Hillman adducts from a-bromoacrylamides and carbonyl compounds. Barbier reaction involving 1-chloromethylbenzotriazole affords alcohols that are valuable synthetic intermediates. iV-(co-Iodoalkyl)-0,0 -bis(f-butyldimethylsilyl)tartrimide undergoes cyclization quite efficiently and the reaction has been applied to a synthesis of (+)-lentiginosine. ... 

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]. 

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