Baylis—Hillman adducts

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. 

Scheme 2.19. Mgl2-mediated synthesis of (3-iodo Baylis-Hillman adducts.

Sitophilate [1-ethylpropyl (2S,3 )-2-methyl-3-hydroxypentanoate, 24] is the male-produced aggregation pheromone of the granary weevil (Sitophilus granarius). Its racemate is also bioactive. Almeida synthesized ( )-24 by diaster eoselective hydrogenation of the Baylis-Hillman adduct A to B as shown in Scheme 37 [60]. This high diastereoselectivity could be observed only with TBS-protected ester A to give pure B. 

Fully substituted furan as depicted below was prepared from a Baylis-Hillman adduct in the presence of sulfuric acid in a moderate yield. Intermolecular Friedel-Crafts reaction is one of steps to give rise to the final tetrasubstituted furan <06T8798>. 

Amino-2,3-dihydrobenzo[fc]furans were obtained employing starting materials generated from Baylis-Hillman adducts <06TL3913>. 

A three-component coupling was used to prepare a series of 1,4-disubstituted-l,2,3-triazoles 129 from the corresponding acetylated Baylis-Hillman adducts 127, sodium azide and terminal alkynes 128 <06TL3059>. This same reaction was also carried out in either water or in... 

Scheme 6.70 Ring-closing metathesis of aza-Baylis—Hillman adducts.

Methylmagnesium bromide (191) exerts a great influence on the stereoselectivity of the reactions between mesitonitrile oxide 10 and the Baylis-Hillman adducts 192. In the absence of a Grignard reagent, a mixture of isomers is formed in which compounds 194 are the main products. The presence of a Grignard reagent reverses the stereoselectivity (Scheme 9.59). When Fisera [107] performed these reactions under microwave irradiation, the reaction times decreased from days to less than 5 min without any loss of stereoselectivity for noncatalyzed cycloadditions, but with a small change in the stereoselectivity in the chelated reactions. 

Dipolar cycloadditions of ( -phenyl-/V-methylnitrone (585) to Baylis-Hillman adducts such as ( 3-hydroxy-a-methylene esters) (608-610) proceed with complete regioselectivity in good yields to afford the corresponding diastere-omeric 3,5,5-trisubstituted isoxazolines (611-613) (Scheme 2.269). Attack by the dipole in (585) from the less sterically hindered side of dipolarophiles (608-610) affords C-3/C-5 cis isoxazolidines (611a,b-613a,b) as the major products (780). 

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. 

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... 

One-pot stereoselective synthesis of trisubstituted E) -2-methylalk-2-enoic acids was performed by treatment of unactivated Baylis-Hillman adducts. This method was used to synthesize three insect pheromones namely,... 

Zinc promoted reduction of Baylis-Hillman adduct derived allylic bromides gave access to... 

The scope was then extrapolated to the two-step three-component aza-Baylis-Hillman setup to obtain (3-amino-a-methylene structures. A two-step approach was chosen to avoid the competition between the aldehyde and the imine for the reaction with the enolate, that would lead to mixtures of Baylis-Hillman and aza-Baylis-Hillman adducts, that is (3-hydroxy and (3-amino esters [87]. 

Some additional examples, where the stereochemical outcome of the cycloaddition to chiral alkenes has been explained in terms of the Honk—Jager model, should also be mentioned. The diastereomer ratio found in the reaction of y-oxy-a,p-unsamrated sulfones (166), with Morita-Baylis-Hillman adducts [i.e., ot-(a -hydro-xyalkyl)-acrylates (167)] (Scheme 6.27), with dispiroketal-protected 3-butene-l,2-diol (168), and with a,p-unsamrated carbonyl sugar and sugar nitroolefin (169) derivatives, all agree well with this model. 

Ab initio calculations also confirm that the use of an allyl magnesium alkoxide in place of the alcohol functionality will lead to high or complete stereoselectivity (138). When homoallylic alcohols are used, the Kanemasa protocol afforded the respective isoxazolines with poor stereoselectivity ( 55 45) in the case of terminal aUcenes, but with very high diastereoselectivity (up to 96 4) in the reaction of cis-1,2-disubstituted olefins (136). Extension of this concept to the reaction of a-silyl allyl alcohols also proved feasible and produced the syn (threo) adducts as nearly pure diastereomers (>94 6) (137). Thus, the normal stereoselectivity of the cycloaddition to the Morita-Baylis-Hillman adducts (anti > syn, see above) can be reversed by prior addition of a Grignard reagent (176,177). Both this reversal... 

Exposure of the Baylis-Hillman adduct 178 to a high-pressure carbon monoxide atmosphere in the presence of a cyclopentadienyliron dicarbonyl dimer (Fp2) catalyst unexpectedly gives small quantities of the A -formylindoline and indolecarboxylate (Equation 114) <2003T747>. 

The formation of rings with more than seven atoms has unfavorable rates because the addition step is often too slow to allow it to compete successfully with other pathways open to the radical intermediate. In stannane based chemistry for example, premature hydrogen abstraction from the organotin hydride is difficult to avoid. However, Baylis-Hillman adducts 111 derived from enantiopure 1-alkenyl (or alkynyl)-4-azetidinone-2-carbaldehydes are used for the stereoselective and divergent preparation of highly functionalized bicycles 112 and 113 fused to medium-sized heterocycles (Scheme 38) [80, 81]. The Baylis-Hillman reaction using nonracemic protected a-amino aldehydes has been attempted with limited success due to partial racemization of the chiral aldehyde by DABCO after... 

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>. 

Acetylated derivatives of Baylis-Hillman adducts derived from ethyl acrylate and aromatic and heteroaromatic aldehydes are synthetically accessible three-carbon fragments that readily react with phenylenediamine under the influence of base to provide l,4-benzodiazepin-2-ones in good overall yield, as depicted in Scheme 71 <2006S4205>. 

The well-known Baylis-Hillman adduct 26 has been exploited to produce dioxepins and dithiepins (Equation 16) <2002JCM366>. 

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... 

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