Ring closures Michael-type

More recently, Tardella and co-workers reported that treatment of 2-trifluorome-thyl acrylate 36 (Scheme 3.12) with the anion generated from nosyloxycarbamate 37 gave rise to aziridine-2-carboxylate 38 in 96% yield and 72% de with undetermined stereochemistry [40]. Aza-MIRC (Michael-initiated ring closure) was used to account for this transformation. A number of other hydroxylamine derivatives have been employed successfully in this type of aziridination reaction, includ-... 

The mechanism for aldehyde-derived enamines involves a Michael-type 1,4-addition of the enamine to the alkenylcarbene complex to generate a zwit-terionic intermediate which evolves to the final product by cyclisation. On the other hand, ketone-derived enamines react through an initial 1,2-addition to the carbene carbon to generate a different zwitterionic intermediate. Then, a [l,2]-W(CO)5 shift-promoted ring closure produces a new intermediate which, after elimination of the metal moiety, furnishes the corresponding cyclopen-tene derivatives (Scheme 30). 

The formation of cyclopropanes from 7C-deficient alkenes via an initial Michael-type reaction followed by nucleophilic ring closure of the intermediate anion (Scheme 6.26, see also Section 7.3), is catalysed by the addition of quaternary ammonium phase-transfer catalysts [46,47] which affect the stereochemistry of the ring closure (see Chapter 12). For example, equal amounts of (4) and (5) (X1, X2 = CN) are produced in the presence of benzyltriethylammonium chloride, whereas compound (4) predominates in the absence of the catalyst. In contrast, a,p-unsatu-rated ketones or esters and a-chloroacetic esters [e.g. 48] produce the cyclopropanes (6) (Scheme 6.27) stereoselectively under phase-transfer catalysed conditions and in the absence of the catalyst. Phenyl vinyl sulphone reacts with a-chloroacetonitriles to give the non-cyclized Michael adducts (80%) to the almost complete exclusion of the cyclopropanes. 

Not surprisingly, electron-poor systems react with chloroform, bromoform and other haloalkanes under basic conditions by Michael-type addition of the trihalomethyl anion to the C=C bond. However, a subsequent base-catalysed ring closure to give the cyclopropane derivatives frequently occurs [e.g., 6,7,26,31,39,72, 84,93,111, 113, 115, 118]. 

Additionally, uracil 6-iminophosphorane, isocyanate, and o-methyl-e-caprolactim ether join to form the intensely yellow pyrimido[4 5 4,5] pyrimido[6,l-n]azepine (360), as shown in Scheme 130. Upon ring closure, methanol is spontaneously eliminated. Diethyl azodicarboxylate affords with the other components pyrimido[4,5-e][l,2,4]triazoline (361), which is closely related to the alkaloid isofervenuline. The imidazo[5, -/][ ,2,4]tria-zine (362) results in a known Michael-type rearrangement sequence by treatment with diethyl acetylenedicarboxylate (86JOC149, 86JOC2787) in this latter case, the Michael-type addition occurs much faster than the expected three-component reaction [93H(35)1055]. 

The two reaction modes of the Michael adducts 145 demonstrate two general principles for the possible preparation of ordinary size heterocyclic compounds from the chlorocyclopropylideneacetates 1,2. Thus, either the heterocycles 153 can be formed by Michael addition of a bidentate nucleophile 150 onto the chloro ester 1-Me and subsequent ring closure of the intermediate 151 [26] by nucleophilic substitution of the chlorine atom at the newly formed sp carbon center adjacent to both the carbonyl and the cyclopropyl group (Route B in Scheme 48). Alternatively, the intermediate 151 can cyclize by nucleophilic attack on the ester moiety to give heterocycles of type 152 (Route A in Scheme 48) [26]. 

Closure of the nonaromatid ring of the anthracycline system has been effected by condensation of a 2-(3-oxobutyl)anthraquinone with nitromethane [135]. After the initial Henry reaction, a Michael-type reaction is induced by the quinone carbonyl in spite of the high electron density of the aromatic ring to be attacked, and the site of attack being a donor. 

The Michael-type addition of an aniline to an unsaturated ester, generated in situ, provided an example of a type a ring closure in which the electrophilic center is sp2-hybridized <2004BML4147>. This reaction represents a synthetically useful procedure to access tetrahydro-1,4-benzodiazepines. 

Reaction of the dilithio anion of 1-vinylbenzotriazole 90 with 2equiv of an aryl isocyanate led to a fused 1,4-diazepine ring formation via an intramolecular Michael addition of the intermediate aryl amide to the vinyl moiety, a type c ring closure that proceeded in good overall yield (Scheme 44) <2003JOC5713>. 

Scheme 9. Key Michael-type quinolizidine ring closure reaction of piperidine 17...

One of the most important classes of Michael initiated ring closure processes in the construction of carbo- and heterocycles are stepwise cycloaddition reactions where a metal induces dipolar behavior in otherwise unreactive organic compounds to be reacted with activated olefins. In this area, Pd-assisted cycloaddition reactions which involve zwitterionic zr-allylPd complexes of type I (linear type), II, or III (Pd-Trimethylenemethane (TMM) type and analogs) as reactive dipole partners are popular methods that provide highly functionalized, saturated ring systems often with high stereocontrol and atom economy (Scheme 1). Discovered in the early 1980s, they have been extensively covered in the review literature [8-16]. 

Gregory, B., Bullock, E., Chen, T.-S. Intramolecular Michael-type additions. A 5-endo-trig ring closure J. Chem. Soc., Chem. Common. 1979, 1070-1071. 

The addition of 4-AI 56 to dimethyl acetylenedicarboxylate on refluxing in ethanol afforded a Michael-type adduct. Ring closure of this product was accomplished by refluxing in xylene for several hours, and 4,5-dihydroisoxazolo[4,5-e][l,4] diazepin-6,8-dione 57 was isolated (87H2419). A convenient route to isoxazolo [4,5-e][l,4]diazepin-8-one 58 was developed, starting from A-methylated amino ester 56 (90G725) (Scheme 24). 

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