Allenes as Substrates

Allenes are versatile synthetic precursors in organic chemistry and the synthesis of many natural products involves the use of allenic compounds [27]. However, they have received much less attention than alkenes or alkynes for transition metal catalyzed reactions. The explanation lies in the problems of selectivity that these substrates display as a result of their reactivity and their inherent chirality [28]. 

Hydroalkoxylation of Allenes In the year 2000, during their investigation of transition metal catalyzed reactions of allenyl ketones [29], Hashmi et al. discovered that gold(III) salts were able to lead the cydoisomerization and dimerization of these substrates (Equation 8.2) with a considerable improvement related to other assays with Ag (I) or Pd (II) catalysts [18]. 

Krause et al. worked on the conversions of 2-hydroxy-3,4-dienoates in the corresponding tri- and tetrasubstituted 2,5-dihydrofuranes by treatment with HCl gas in chloroform. Since this reaction was not accessible with acid-labile substrates [30,31], these conversions were tested through gold catalysis, obtaining better reaction rates and transformations in more difficult substrates compared to the well-established Ag(I)-promoted method [32]. 

Some years later, this activation was also applied in the synthesis of new 2,5-dihydrofuranes from allenamide. This reaction was achieved without loss of stereochemistry and with good yields [33]. 

This method was also tested with the P-aminoallene 19 and a slow but dean conversion into the tetrahydropyridine 20 was observed. 

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Most gold-catalyzed reactions involve this pattern of reactivity that has been studied since the eighties. The first examples were found with allenes as substrates and subsequently alkenes and alkynes started to be used, the latter being the most popular in the last five years. 

In early investigation of the reactions of allenes with transition metals, the conversions proceeded quite unselectively due to the enhanced reactivity of the allenes [1]. This observation led to the neglect of allenes as substrates in such reactions for a long time. In the past... 

Cumulenes such as allenes also react with MCP in the presence of palladium(O) catalysts. With allene as substrate, 5-methylenespiro[2.4]heptane (23% yield) can be obtained along with the [3-h2] cycloadduct, l,3-bis(methylene)cyclopentane, in 40% yield. A third product of the reaction, however, is a [3-I-2-I-2] cycloadduct (see Section 2.2.2.3.3.). When the less reactive 1,1-dimethylallene (12) is employed, no [3 -I-2-L2] adduct is formed. Instead, the [3-f 2] adduct, l-methylene-3-(l-methylethylidene)cyclopentane (13), can be obtained in 11-25% yield, depending on the specific catalyst.The major product is 5-methylenespiro[2.4]heptane (7), while 2,5-dimethyl-3-methylenehexa-l,5-diene (14) and dimethylallene trimers are additionally formed. 

A number of Pd-catalyzed carbonylative processes have employed allenes as substrates for the synthesis of nitrogen heterocydes [108], For example, subjection of substituted allene 170 to reaction conditions similar to those employed in related reactions of alkenes led to the formation of pyrrolidine 171 in 68% yield with 2 1 dr (Eq. (1.67)) [108d], Modest asymmetric induction has been achieved in these transformations using simple chiral auxiliaries [108b,d]. This strategy was employed in an asymmetric synthesis of pumiliotoxin 251 D, which involved the aminocarbo-nylation of allene 172 to pyrrolidine 173 as a key step (Eq. (1.68)) [108b]. 

Conceptually similar palladium-catalyzed cascade reactions have been developed, involving molecular-queuing cycloaddition, cyclocondensation and Diels-Alder reactions [71], cydization-anion-capture-olefin metathesis [72], carbonylation-allene insertion [73], carbonylation/amination/Michael addition [74], sequential Petasis reaction/palladium-catalyzed process [75], supported allenes as substrates [76], and palladium-ruthenium catalysts [77]. 

A generally accepted mechanistic framework with allenes as substrates involves formation of 71-allyl-Pd complex. The formation of the allyl derivatives in the P-H bond addition reaction agrees well with the mechanism of hydropalladation (Scheme 8.21). 

When perfluoroheptylcopper reacted with propargyl bromide, a violent reaction occurred, and less than 10% of the expected allene was obtained [226] However, when propargyl chlorides or tosylates were used as substrates, the expected allenes were obtained m good yields [227] (equation 156)... 

Instead of alkynes, allenes can also be used as substrates in this type of approach. Finally, one can also apply carbon-nucleophiles such as butadienes in this domino process. Thus, Lu and Xie [145] have treated the alkyne 6/1-303 with an aryl halide 6/1-304 and an amine 6/1-305 to give the substituted pyrrolidinone 6/1-308 via the proposed intermediates 6/1-306 and 6/1-307. As a side product, 6/1-309 is found to have been formed by a cycloaddition of 6/1-303 (Scheme 6/1.81). 

The unique combination of double bonds in the molecules of those compounds, each with different reactivity along with the easy preparation, makes phosphorylated allenes useful substrates for the synthesis of different cyclic and noncyclic organophosphorus compounds. Recent investigations increase the scope of application of phosphorylated allenes as precursors in organic syntheses. Most of them are accompanied by the formation of five- or six-membered phosphorus heterocycles, which in many cases demonstrate certain biological activity. 

As mentioned in the Introduction, this chapter focuses on reactions that deliver allenes as the product. The principles discussed in Sections 1.2.1-1.2.9, of course, also allow the synthesis of allenes as reactive intermediates, which due to other functional groups that are present, undergo further reactions in situ. The most important examples here are base-catalyzed isomerizations to furans [347, 348] ring transfer reactions of propargylic ethers or amines [216, 349-371] and enyneallene cycliza-tion reactions starting from propargylic sulfones [372-375] and related substrates [376, 377]. Details are discussed, for example, in Chapters 16 and 20. 

In 1994, Badone et al. reported that the Stille coupling of allenylstannane 77 and aryl triflates 78 resulted in formation of various aryl-substituted allenes 79 in moderate to good yield (Scheme 14.18) [39]. The choice of catalyst was certainly a crucial issue in this process for optimizing yield and rate. The best results could be obtained employing a catalyst cocktail of Pd2(dba)3-TFP-LiCl-CuI. Similar Stille coupling reactions with stannylated allenes and aromatic iodides as substrates were described by Aidhen and Braslau [40a] and Huang et al. [40b],... 

Allenic tripetides as substrates foriso-penicillin-N synthetase J. E. Baldwin,... 

Allenes have also been used as substrates in free radical cyclizations. Dener and Hart demonstrated that such entries are valuable in constructing pyrrolizidine and indolizidine ring systems [71]. In a total synthesis of pyrrolizidine base (+)-heliotri-dine (340), compound 338 possessing an allene functionality was used as a key intermediate (Scheme 19.62). Tri-n-butyltin radical-mediated carbon-selenium bond homolysis of 338 followed by the addition of the free radical to the allene moiety... 

The intermolecular [2 + 2]-photocycloaddition of para-tetrahydronaphthoqui-nones has been applied by Ward et al. to the synthesis of cyathin diterpenes [52], An example is represented by the total synthesis of ( )-allocyathin B3 (46), during the course of which the diastereoselective [2 + 2]-photocycloaddition of allene to substrate 44 served as one of the pivotal steps (Scheme 6.17) [53]. The addition delivered a mixture of regioisomers (r.r. = 80/20), from which compound 45 was separated. The facial diastereoselectivity was perfect due to the concave shape of the quinone. 

To understand the carbanion mechanism in flavocytochrome 62 it is useful to first consider work carried out on related flavoenzymes. An investigation into o-amino acid oxidase by Walsh et al. 107), revealed that pyruvate was produced as a by-product of the oxidation of )8-chloroalanine to chloropyruvate. This observation was interpreted as evidence for a mechanism in which the initial step was C -H abstraction to form a carbanion intermediate. This intermediate would then be oxidized to form chloropyruvate or would undergo halogen elimination to form an enamine with subsequent ketonization to yield pyruvate. The analogous reaction of lactate oxidase with jS-chlorolactate gave similar results 108) and it was proposed that these flavoenzymes worked by a common mechanism. Further evidence consistent with these proposals was obtained by inactivation studies of flavin oxidases with acetylenic substrates, wherein the carbanion intermediate can lead to an allenic carbanion, which can then form a stable covalent adduct with the flavin group 109). Finally, it was noted that preformed nitroalkane carbanions, such as ethane nitronate, acted as substrates of D-amino acid oxidase 110). Thus three lines of experimental evidence were consistent with a carbanion mechanism in flavoenzymes such as D-amino acid oxidase. 

The temperature and solvent dependence for allene production is seen in the buta-1,3-dienyl)cyclopropylidene rearrangement carried out under three different sets of reaction conditions, e.g. reaction with 16, 17 and 18 as substrates. ... 

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