Enynes benzannulation reactions

The fact that pentacarbonyl carbene complexes react with enynes in a chemo-selective and regiospecific way at the alkyne functionality was successfully applied in the total synthesis of vitamins of the Kj and K2 series [58]. Oxidation of the intermediate tricarbonyl(dihydrovitamin K) chromium complexes with silver oxide afforded the desired naphthoquinone-based vitamin K compounds 65. Compared to customary strategies, the benzannulation reaction proved to be superior as it avoids conditions favouring (E)/(Z)-isomerisation within the allylic side chain. The basic representative vitamin K3 (menadione) 66 was synthesised in a straightforward manner from pentacarbonyl carbene complex 1 and propyne (Scheme 38). 

A Dotz benzannulation reaction was utilized in the synthesis of the furo[2,3- >]furan core of aflatoxin B2 as illustrated below <06TL2299>. Synthesis of polynuclear aromatic compounds was achieved by using [5+5] cycloaddition of 2-alkynylarylcarbene complexes and enyne-aldehyde derivatives <06TL5303>. 

A completely new benzannulation reaction of conjugated enynes and alkynes catalysed by Pd complexes to give substituted benzenes has been developed recently. When the 1,3-enyne 150 is treated with a Pd(0) catalyst, homocyclodimerization of the enyne takes place to give the 2,6-disubstituted styrenes 151 as a single product in good yield [64], An interesting application of this reaction is the preparation of paracyclophane 153 by the intramolecular reaction of the bis-enyne 152 [65],... 

Saito S, Yamamoto Y (2002) Palladium-Catalyzed Benzannulation Reactions of Conjugated Enynes and Diynes. In Negishi E, de Meijere A (eds) Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley, New York, p 1635... 

Inter- and intramolecular palladium-catalyzed [4 - - 2] homocycloaddition reactions (i.e., benzannulation reaction) of conjugated enynes and bis-(enynes) have been reported by Yamamoto and co-workers (10, 507-509). Reaction of two-substituted conjugated enynes in the presence of Pd(PPh3)4 (2mol%) smoothly undergoes [44-2] intermolecular homocycloaddition to afford 1,4-disubstituted benzenes in good yields (10) (Scheme 73). 

IV.10.2 Palladium-Catalyzed Benzannulation Reactions of Conjugated Enynes and Diynes... 

The scope of the reaction discussed in Sect. B is somewhat limited since the only practical synthetic procedure consists of the cyclodimerization of the two identical enynes, and therefore the same substituents are attached at the phenyl group and the vinyl group of the reaction product. The attempted cross-annulation of conjugated enynes with alkynes or dienes turned out to be unsuccessful. However, the scope of the benzannulation reaction could be extended significantly by introducing conjugated... 

SCHEME 14.2 Transition-metal-catalyzed benzannulation reactions of conjugated enynes with alkynes. 

BENZANNULATION OF ENYNE WITH ALKYNE GOLD-CATALYZED BENZANNULATION REACTION... 

Transition-metal-catalyzed [4 -I- 2] benzannulation reaction of enyne with alkyne enynophile was reported by Toste group [6]. The reaction between enynes 4 and propargyl ethers 5 in the presence of a gold catalyst led to the formation of multisubstituted arenes 6 via a formal [4-1-2] cross-benzannulation reaction (Scheme 14.3). 

SCHEME 143 Au-catalyzed formal [4 + 2] benzannulation reaction of enynes and alkynes. 

SCHEME 14.7 Pd-catalyzed [4 + 2] homo-benzannulation reaction of monosubstituted enynes. 

Homo-benzannulation reaction of di- or trisubstituted enynes is a less facile process [7b,c]. Thus, neither 1,2- nor 2,4-dialkyl enynes underwent homo-benzannulation... 

TABLE 14.1 Pd-Catalyzed [4 + 2] Homo-benzannulation Reaction of Electron-Neutral 2,4-Disubstituted Enynes... 

The reactivity of enynes toward the Pd-catalyzed [4 + 2] homo-benzannulation reaction depends on both electronic and steric properties of the substrate. The reaction is more facile with electron-deficient substrates. Substitution at the second position of enyne generally promotes a benzannulation reaction, whereas 1-substituted substrates are least reactive. Reactivity also becomes lower as the number of substituents increases. 

The difference in enyne reactivity allowed for control of selective cross-benzannulation reaction between two enynes [9] (Scheme 14.10). Thus, reaction between highly active electron-deficient enynes A and less reactive enynes B occurred in a regio- and chemoselective manner, which was achieved via a slow addition of more reactive enyne. Notably, only one isomer of two potential cross-benzannulation products was generally obtained. 

Nakao et al. developed a metallative version of the Pd-catalyzed [4 + 2] benzannu-lation reaction [10], They have demonstrated that benzannulation reaction of enynes in the presence of bis(tributyl)tin oxide offers easy access to the 3-alkenylarylstannanes (Scheme 14.11). Reaction was shown to proceed with good yields for a variety of monosubstituted enynes, whereas the amount of nonstannylated by-product varied from 4 to 30%. 

Additionally, the metallative version was also applicable to the cross-benzannulation reaction between two different enynes (Scheme 14.12). 

SCHEME 14.12 Stannylative Pd-catalyzed [4 -I- 2] cross-benzannulation reaction of two enynes. 

One of the common ways of accessing enynes is the Sonogashira cross-coupling reaction between vinyl bromides and terminal acetylenes. Based on that, a cascade transformation for the Pd-catalyzed [4 - - 2] benzannulation reaction between two... 

Interestingly, under the same reaction conditions the benzannulation reaction did not take place in the case of electron-deficient substrates such as 36, providing the corresponding alkyne trimerization product 37 instead (Scheme 14.16). These results highlight the difference between cobalt- and palladium-catalyzed benzannulation reactions, where electron-poor enynes were the most reactive substrates for the [4 - - 2] benzannulation reaction. 

Shortly after palladium-catalyzed [4-1-2] homo-benzannulation reaction of two enynes was discovered [4], a cross-benzannulation of enynes with diyne enynophiles was developed [13], thus substantially expanding the scope of this transformation. Similar to the homo-benzannulation reaction, the cross-benzannulation reaction occurs in a highly regioselective manner, offering easy access to densely substituted arylacetylenes 10 as solo regioisomers (Scheme 14.17) [13,14]. In most cases, the reaction is chemoselective, providing a product of cross-benzannulation reaction only. 

In a manner analogous to the palladium-catalyzed [4 -l- 2] benzannulation reaction of two enynes, the stannylative version of the benzannulation reaction of enyne with diyne was also successful, providing 3-alkynylarylstannane 40 in 85% yield [10] (Scheme 14.18). Notably, the metallative version of this reaction made it possible to introduce substitution at the mefa-position to the alkynyl moiety, which is the only nonfunctionalizable position via the nonmetallative method. 

A highly atom-economical cascade transformation employs Trost s Pd-catalyzed dimerization of alkynes [15] and consequent Pd-catalyzed benzannulation reaction [16] (Scheme 14.20). A formal [2 - - 2 - - 2] cycloaddition reaction proceeded through the formation of 2,4-enyne followed by a formal [4 - - 2] benzannulation reaction with diyne, representing a highly chemo- and regioselective trimerization reaction of alkynes. Homo-dimerization of terminal acetylenes followed by a benzannulation... 

Similarly, a variety of aryl ethers can be obtained via the [4-1-2] cross-benzannulation reaction of enynes with diynes (Scheme 14.24) [18]. Notably, using this strategy, alkoxy substituent can be introduced at positions 2, 4, and 6 of ary-lacethylene 65 with the use of appropriate coupling partners. Moreover, starting from silyl ethers, the corresponding p-alkynylphenols can be synthesized after deprotection in either a stepwise or a one-pot fashion [18b],... 

Phosphine oxides are among various functionalities that can be introduced into aromatic alkynes via a Pd-catalyzed benzannulation reaction. Thus, the reaction between readily available enynes 70 with 5,7-dodecadiyne resulted in the formation of the corresponding benzylphosphine oxide 71 in good yields [20] (Scheme 14.28). 

Besides the wide use of the Pd-catalyzed [4 - - 2] benzannulation reaction to the direct synthesis of adducts with desired functionalities, it was also employed for the late-stage derivatization of molecules of interest. For example, novel quinucli-dine derivatives were prepared via this methodology [22]. Thus, enyne-containing quinuclidine derivatives underwent benzannulation reaction to fonnpenta substituted benzene 82 in a fair yield. On the other hand, formal [2 -p 2 -p 2] benzannulation of phenylacethylene with diyne, possessing quinuclidine moieties, furnished an aromatized product with good efficiency (Scheme 14.31). 

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