Oxo-Michael reaction

A broad range of enantiomericaUy pure 4,5-dihydrobenzo[r [l,3]diox-epines 177 have been prepared via a four-component Mannich reaction and subsequent intramolecular oxo-Michael reaction (14CC2196). The reactions proceeded with both high enantio- and diasteroselectivity, utilizing a dual catalytic system of Rh2(OAc)4 and a chiral phosphoric acid 178. The rhodium catalyst forms the protic oxonium ylide 174 from a diazo compound 171 and this subsequently adds to imine 175, formed in situ. The resulting enantiomericaUy enriched intermediate 176 then undergoes an intramolecular and diastereoselective oxo-Michael addition to form the final product 177. 

However, despite success in several tandem reactions, or in epoxidation reactions, there are only a few examples in the literature of simple oxo-Michael reactions with enals. 

The first enantioselective organocatalytic oxo-Michael reaction to enones was reported by Falck [109]. Falck developed the intramolecular addition of boronic acids hemiesters to enones catalyzed by thiourea catalysts. Alkyl, aryl, and heteroaryl y-hydroxy enones react with phenylboronic acid to furnish the corresponding boronic hemiesters 118, which after oxidative cleavage of the resulting dioxaboro-lane renders the chiral 1,2 diols 119 in excellent yields and enantioselectivities (Scheme 33.34). 

Scheme 33.36 Oxo-Michael reaction of enones reported by List.

You and coworkers developed a desymmetrization protocol based on an intramolecular oxo-Michael reaction, using as catalyst the phosphoric acid derivative 121 [110]. Cyclohexadienones 120 were transformed into the corresponding bicyclic systems 122 with high yields and enantioselectivities. Remarkably, the 4-substituent in the cyclohexadienone has a great influence on the enantioselective outcome of the reaction. Bulkier substituents at the 4-position lead to lower reaction rates and enantioselectivities (Scheme 33.35). This desymmetrization reaction was used as a key reaction for the efficient synthesis of the natural products cleroindicins C,... 

Aminobenzenethiol undergoes a Michael reaction with methyl 5,5-dimethyl-2-oxo-2,5-dihyd-rofuran-3-carboXylate (4) to give the adduct 5, which cyclizes to the tricyclic benzothiazepinone 6 under the influence of triethylamine hydrochloride.426... 

Scheme 2.32 Ni-catalysed Michael reaction of p-oxo ester with methyl vinyl ketone...

Atracurium Atracurium is 2,2 -[l,5-pentanediylZtM[oxy(3-oxo-3,l-propanediyl)]] bis [l-[(3,4-dimethoxyphenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquino-Unium] dibenzene sulfonate (15.1.12). This compound is synthesized from (tw-acrylic ester of 1,5-pentandiol (15.1.10), which is synthesized from acrylic acid chloride and 1, 5-pentandiol. Two molecules of a secondary amine, tetrahydropapaverine, are joined to the product in a Michael reaction, forming compound (15.1.11). Then both nitrogen atoms are methylated by methylbenzenesulfonate, giving atracurium (15.1.12) [17-19]. 

Michael Reaction. 5(47/)-Oxazolones undergo base-catalyzed conjugate addition to activated unsaturated compounds to afford the corresponding C-4 Michael adducts. For example, base-catalyzed addition of a 4-monosubstituted-5(4//)-oxazolone 157 to methyl propiolate yields a mixture of diastereomeric methyl 3-(5-oxo-2-phenyl-2-oxazolin-4-yl)acrylates 158. Hydrolytic ring opening of 158 and subsequent oxidation with lead tetraacetate affords 3-acylacrylates 160... 

In contrast, ethyl 3-oxo-4-(triphenylphosphoranylidene)butyrate behaves as a C,0-bis(nucleophile) when reacted with unsaturated 5(4//)-oxazolones 584 with a leaving group at the exocyclic p-carbon. In this case, initial Michael reaction generates 585 that eliminates HX to produce a resonance stabihzed ylide 586. Cyclization of 586 with ring opening leads to the interesting ylide intermediate 587 used for the synthesis of 2//-pyran-2-ones (Scheme 7.185). 

Michael reactions of chiral lithioenamines of p-oxo esters with dimethyl alkylidenemalonates were studied.173-176 Especially the a-alkyl-substituted compounds (161) and (163), derived from L-valine t-butyl ester, afford, after hydrolysis, the adducts (162) and (164), respectively, diastereoselectively and with high ee (Scheme 57).175 In the presence of TMS-C1, even weaker acceptors like acrylates or MVK were shown to react.176 A somewhat related diastereoselective 1,4-addition, followed by a Pictet-Spen-gler-type cyclization, allows the preparation of compound (165 Scheme 58),177 a central intermediate for the synthesis of several alkaloids.177-178... 

Scheme 8.14 Michael reaction of p-diketones (X = alkyl) and p-oxo esters (X = alkoxy) with methyl vinyl ketone (41a, MVK).

Fe(III)-exchanged fluorotetrasilicic mica acts as a highly effective and reusable catalyst for solvent-free Michael reactions of P-oxo esters with MVK (41a). The immobilized catalyst shows higher activity than homogenous Fe(III) catalysts. Product 42a (cf. Scheme 8.27), for example, is formed in 99% yield even if the catalyst is reused four times [92]. 

An intramolecular tandem Michael aldol reaction was described for esters that have an enolizable aldehyde in the molecule. The lithium ester enolate generated through the Michael reaction undergoes an intramolecular aldol reaction. Thus, the reaction of unsaturated esters 153 with lithium benzylthiolate provided the expected cyclization products 156 and 157 via (w-formylenolate 154 in an excellent cis stereoselectivity (Scheme 49)no. 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

Ethyl 2-(3-phenyloxiran-2-yl)-4-oxo-3,4-dihydroquinoxaline-3-propanoate was similarly de-alkylated with methanolic sodium methoxide via a retro-Michael reaction to give 2-(l,2-epoxy-2-phenylethyl)quinazolin-4(3//)-onc. ... 

The most commonly used type of catalyst is a relatively small, bifunctional molecule that contains both a Lewis base and a Bronsted acid center, the catalytic properties being based on the activation of both the donor and the acceptor of the substrates. The majority of organocatalysts are chiral amines, e.g. amino acids or peptides. The acceleration of the reaction is either based on a charge-activated reaction (formation of an imminium ion 4), or involves the generalized enamine catalytic cycle (formation of an enamine 5). In an imminium ion, the electrophilicity compared to a keton or an oxo-Michael system is increased. If the imminium ion is deprotonated to form an enamine species, the nucleophilicity of the a-carbon is increased by the electron-donating properties of the nitrogen. ... 

Transition metal catalysis of the Michael reaction of 1,3-dicarbonyl compounds with acceptor activated alkenes has been known since the early 1980 s 2>3 It is a valuable alternative to the classic base catalysis of the reaction. Because of the mild and neutral conditions, the chemoselectivity of these reactions is superior to that provided by base catalysis, since the latter suffers from various unwanted side or subsequent reactions, such as aldol cyclizations, ester solvolyses or retro-Claisen type decompositions. A number of transition metal and lanthanide compounds have been reported to catalyze the Michael reaction, but FeCb 6 H20 is one of the most efficient systems to date. A number of 3-diketones or p-oxo esters and MVK are cleanly converted to the corresponding Michael reaction products within a few hours at room... 

Michael reaction of two molars of 1 and diarylideneacetone in a mixture of boiling toluene and n-heptane in the presence of anhydrous ZnCl2 afforded 2,2 -spirobis(4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-chromane) 464 (05TL8217) (Scheme 96). 

The amine-immobilized silica-alumina catalyst achieved a good yield of 2-cyano-5-oxo-2-(3-oxobutyl) hexanoic acid ethyl ester from the Michael reaction between nitrile and a,P-unsaturated ketone (Table 7.6). Notably, the reaction using a mixture of triethylamine and unfunctionahzed sihca-alumina gave a lower yield than the amine-immobilized silica-alumina, and both triethylamine and silica-alumina were inactive alone for the reaction. In general, the conjugate addition of nitrile compounds to a,P-unsaturated ketones requires strong base or transition metal... 

Nishida and Nakagawa [80-82], Langlois [83,84], Simpkins [85] and Mara-zano [86,87] have used the intermolecular Diels-Alder reaction to synthesize the central core of manzamine A (Scheme 12). We have also demonstrated that an efficient Diels-Alder reaction using Danishefsky-type siloxydiene (125) followed by acid treatment resulted in a Michael reaction to give the chiral ABC ring intermediate (122) of manzamine A (Scheme 12). This intermediate was converted to 36-oxo-ircinal A (119) using sequential RCM to prepare the D- and E-rings. 

Under presented conditions (triazolium bromide XI and DBU in CHjCy, the reaction proceeds by a cascade reaction (i) first, amidation (aza-benzoin condensation between enal and nitrosoarene, as outlined in Scheme 5.33) produces A-hydroxyacrylamide 51, and (ii) second, in the presence of base such as DBU or triazole carbene [41], oxo-Michael addition of 51 to enones would afford products 52 (Scheme 5.35). 

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