Allenes Michael addition

A typical second step after the insertion of CO into aryl or alkenyl-Pd(II) compounds is the addition to alkenes [148]. However, allenes can also be used (as shown in the following examples) where a it-allyl-r 3-Pd-complex is formed as an intermediate which undergoes a nucleophilic substitution. Thus, Alper and coworkers [148], as well as Grigg and coworkers [149], described a Pd-catalyzed transformation of o-iodophenols and o-iodoanilines with allenes in the presence of CO. Reaction of 6/1-310 or 6/1-311 with 6/1-312 in the presence of Pd° under a CO atmosphere (1 atm) led to the chromanones 6/1-314 and quinolones 6/1-315, respectively, via the Jt-allyl-r 3-Pd-complex 6/1-313 (Scheme 6/1.82). The enones obtained can be transformed by a Michael addition with amines, followed by reduction to give y-amino alcohols. Quinolones and chromanones are of interest due to their pronounced biological activity as antibacterials [150], antifungals [151] and neurotrophic factors [152]. 

Lower order cyanocuprates RCu(CN)Li displayed again a different behavior although they usually do not react with acceptor-substituted enynes, the cyanocuprate tBuCu(CN)Li nevertheless underwent anti-Michael additions to 2-en-4-ynoates (e.g. 70) and nitriles affording allenes of type 73 (Scheme 2.26) [51]. Unfortunately, an adequate interpretation of the abnormal behavior of this particular cuprate is still lacking. 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

Pharmacologically active allenic steroids have already been examined intensively for about 30 years [5], Thus, the only naturally occurring allenic steroid 107 had been synthesized 3 years before its isolation from Callyspongia diffusa and it had been identified as an inhibitor of the sterol biosynthesis of the silkworm Bombyx mori (Scheme 18.34) [86d], At this early stage, allenic 3-oxo-5,10-secosteroids of type 108 were also used for the irreversible inhibition of ketosteroid isomerases in bacteria, assuming that their activity is probably caused by Michael addition of a nucleophilic amino acid side chain of the enzyme at the 5-position of the steroid [103, 104]. Since this activity is also observed in the corresponding /3,y-acetylenic ketones, it can be rationalized that the latter are converted in vivo into the allenic steroids 108 by enzymatic isomerization [104, 105],... 

During the last decade, a substantial number of novel (sometimes even stereoselective) strategies for the preparation of allenic prostaglandins have been devised. The approach used by Patterson involves a three-component coupling via a 1,4-addi-tion of the organocopper compound 121 to the enone 120, followed by alkylation of the enolate formed with the bromide 122 (Scheme 18.40) [121]. However, due to the notoriously low reactivity in the alkylation of the mixed copper-lithium enolate formed during the Michael addition [122], the desired product 123 was obtained with only 28% chemical yield (the alkylation was not even stereoselective, giving 123 as a 1 1 mixture of diastereomers). 

Additional routes to a-allenic-a-amino acids were described more recently and utilize radical [136] or transition metal-catalyzed [137] allenylations, in addition to copper-promoted Michael additions [15b]. Thus, sterically demanding amino acid derivatives (e.g. 151) are accessible via a 1,6-addition reaction of lithium di-tert-butyl-cyanocuprate with acceptor-substituted enynes of type 150 (Scheme 18.48). 

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

As in the case of addition reactions of carbon nucleophiles to activated dienes (Section HA), organocopper compounds are the reagents of choice for regio- and stereoselective Michael additions to acceptor-substituted enynes. Substrates bearing an acceptor-substituted triple bond besides one or more conjugated double bonds react with organocuprates under 1,4-addition exclusively (equation 51)138-140 1,6-addition reactions which would provide allenes after electrophilic capture were not observed (cf. Section IV). 

For the most part, alkynic and allenic ketones have found limited use in conjugate addition-enolate trapping sequences 69,81-83 their analogous esters have been used with far greater frequency (vide infra). Alkynic ketones, in particular, have found use in development of a new anionic polycyclizadon method consisting of intramolecular Michael addition followed by intramolecular alkylation (equation 15).84... 

More recently, the synthesis of 3-norcephalosporin 72 has been performed successfully by reaction of either allenoate 70 or 3,4-disubstituted 2-butenoates 73a and 73b with copper(i) chloride and tributyltin hydride in NMP <1996GG2705, 1999J(P1 )3463>. Conversion of the allenoate 70 into 72 took place through Michael addition of copper(l) hydride to the central carbon of the allene moiety of 70 and subsequent ring closure of adduct 71. The sequential reaction could be performed successfully by treatment of 70 with copper) 0 chloride and tributyltin hydride in NMP at room temperature, affording 72 in 79% yield without any detectable amount of the A2-isomer (Scheme 16). 

In a [4+2] cycloaddition reaction that proceeds via a Michael addition, an azadiene has been shown to react with Fischer carbenes yielding the 1,4-dihydropyridine after removal of the metal (Scheme 82) <1997TL3981>. Reactions of 1-azadienes with allenic esters yield the 1,4-dihydropyridine in excellent yield (Scheme 83) <20010L2133>. 

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

The activation of allenes is a rather new, but particularly promising area of gold catalysis.381,400 The first example for such a transformation is the cycloisomerization of allenic ketones 480 to furans 482 which probably occurs via intermediate 481 (Scheme 147). Hashmi et /.401,401a showed that this reaction proceeds much faster when gold(m) chloride in acetonitrile is employed as the precatalyst instead of the traditionally used silver salts (cf. Section 9.12.3.2). The products are usually contaminated by substituted furans originating from a Michael addition of aurated 482 to the substrates 480, thereby indicating that the gold catalyst is also capable to activate C-H bonds of furans. 

An alternative pathway for the above reactions has also been proposed by the authors, involving first a Michael addition of the nucleophile, followed by a subsequent interception of the palladium intermediate species. Nevertheless, the authors opinion is in favor of the first mechanism as proved, in a control experiment, by no isolation of Michael adduct when benzylamine was used as the sole reagent and in the absence of carbon monoxide. In the case of allene, when malonitrile was used as the nucleophile (YH2) and the reaction stopped before completion, a mixture of intermediate 104 and final product was isolated giving an evidence for the proposed mechanism. 

Primary amines reacted via a palladium-catalysed allene insertion-nucleophilic incorporation-Michael addition cascade to give isoquinoline derivatives. The yields were good and fifteen examples are reported <03TL7445>. 

Treatment of an allene amine with a ruthenium catalyst, 10% of TiCl4 and methyl vinyl ketone to give a product of amine addition followed by Michael addition, a... 

Altenbach used the Michael addition of sodium methyl malonate to allene (206) for a dia-stereoselective spiroannulation to a steroid (equation 72). Or, in imaginative work by Okamura, allenyl sulfoxides were transformed into enantiomerically pure hydrocarbons by pericyclic reactions like electrocyclic ring closure (equation 73) or intramolecular cycloaddition (equation 74). Note that the starting materials (propargylic alcohols) are readily accessible as single enantiomers. 

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