Aryne cyclotrimerization

Scheme 40. Infermolecular [2 + 2 + 2] cyclotrimerization of reactive aryne and alkyne intermediates [137c, 138,139 c]...

These catalytic cyclotrimerizations of alkynes can be promoted by many transition metals. Complexes of Ni, Pd, Pt, Rh and, in particular, Co have found wide application in organic synthesis. However, even by the end of the 1990s very little was known about similar cyclotrimerization reactions of arynes. The formation... 

In 1998, Guitian, Perez and co-workers reported that the cyclotrimerization of benzyne (1) to triphenylene (56) is efficiently catalyzed by palladium(O) complexes (Scheme 11) [39]. This was the first time an aryne had been the substrate in a metal-catalyzed process. The success of the reaction was based on a judicious choice of the reaction conditions, particularly with regard to the catalytic system and the method of generating the aryne. Some significant results of this seminal study are shown in Table 1. After some preliminary experiments in which nickel complexes were used as catalysts (entry 1), it was found that nucleophilic palla-dium(O) complexes efficiently promote the desired [2+2+2] cycloaddition of the strongly electrophilic substrate 1 (entries 2-6) [40]. At the same time, a systematic study of benzyne generation conditions showed that Kobayashi s method... 

The use of precursors of asymmetrically substituted arynes introduces the question of regioselectivity, since two products of cyclotrimerization are possible. However, the cyclotrimerization of asymmetrically substituted aryne 2, generated from 3-methoxy-2-(trimethylsilyl)phenyl triflate (64), proceeds in good yield and with high regioselectivity, affording a 93 7 mixture of regioiso-mers 65 and 66 (Scheme 14) [39]. 

For the palladium-catalyzed cyclotrimerization of arynes, a mechanism similar to the accepted mechanism for [2+2+2] cycloaddition of alkynes may be proposed (Scheme 15). Though it has not been studied in depth, some experimental results support it. Firstly, aryne-forming conditions are necessary for the reaction to proceed (see Table 1, entry 8) no reaction of trifiate 55 takes place at room temperature in the presence of the catalyst if fluoride is absent, which rules out a mechanism initiated by the oxidative addition of the aryl trifiate to palladium. Data obtained in the closely related cocycloadditions of benzyne with alkynes, discussed below, hkewise point to benzyne as the reactive species. Secondly, the benzyne-palladium complex 67 is a plausible initial intermediate because the ability of group 10 metals to coordinate benzyne is well known (see Sect. 1.2.2), and although benzyne complexes of palladium have eluded isolation (apparently because of their instability) [7,26], they may well be able to exist as transient intermediates in a catalytic cycle such as that shown in Scheme 15. Thirdly, it is known that benzyne complex 34 can form metallacy-cles similar to 68, albeit with dcpe as hgand instead of PPhj [26]. 

Regarding the regioselectivity of the cyclotrimerization of the asymmetrically substituted aryne 2, further experimental work and/or calculations are needed to find a rational explanation. It is not a trivial problem. If the cyclotrimerization of 2 proceeds via the mechanism of Scheme 15, intermediates 69,70 and 71 might be formed (Scheme 16). All three can be transformed into 65, but 66 can only be formed from 69. 

The palladium-catalyzed cyclotrimerization reaction is not limited to mono-cyclic arynes. On the contrary, a very interesting field of application of this reaction is the synthesis of extended PAHs from polycyclic aryne precursors. 

The synthesis of HBT (73), which contains three [5]helicene units, illustrates the power of the cyclotrimerization of polycyclic arynes for the synthesis of he-licenes. More examples are shown in Table 2. Again, Pd2(dba)3 is the catalyst of choice for trimerization of the asymmetric arynes 77-79, which are generated from the corresponding o-(trimethylsilyl)aryl triflates 74-76. In the reactions of 1,2-didehydronaphthalene (77) and 1,2-didehydrophenanthrene (78), mixtures of regioisomers are obtained, whereas 84 is the only isomer isolated from the cyclotrimerization of 79. Compounds 80 and 82 contain a [5]helicene unit, while compound 84 is the first example of a double helicene formed by a pen-tahelicene and a heptahelicene with two rings in common. 

The palladium-catalyzed cyclotrimerization of arynes can also be used to construct flat hydrocarbons with extended conjugation, such as hexabenzotri-naphthylene (supertriphenylene, 87). In this case the required aryne 86 was generated in the presence of palladium by treatment of triflate 85 with tetra-butylammonium fluoride, and afforded trimer 87 in 20% isolated yield from 85 (Scheme 18) [51]. As in other cases (see below), the use of a soluble fluoride source was necessary because the extended planar reaction product is extremely... 

Table 2 Palladium-catalyzed cyclotrimerization of asymmetric polycyclic arynes...

Now analysis of the literature on palladium-catalyzed cyclotrimerizations suggests that arynes and alkynes have very different reactivities while arynes, which are strongly electrophilic, are efficiently cyclotrimerized by Pd(0) catalysts [ 39 ], there are few examples of efficient cyclotrimerization of alkynes using these complexes [61,62]. This difference in reactivity between arynes and alkynes in Pd-catalyzed cyclotrimerizations, rather than being a disadvantage, provides the chemoselectivity required for their cocyclization to be synthetically useful. Interestingly, cocyclizations of arynes and alkynes frequently show marked dependence on factors such as the electronic nature of the alkyne, the catalyst structure, or the reaction conditions. 

Scheme 35) [70]. As in the cyclotrimerizations of arynes, there is no clear explanation for the regioselectivity of this reaction. 

Recently, the Yamamoto group and the Guitian group as pioneers in this field have developed efficient Pd-catalyzed reactions of arynes, particularly cyclotrimerization and cocyclization with alkynes, offering useful synthetic methods for polycyclic aromatic compounds [78]. The Spanish group reported that the cyclotrimerization of benzyne, generated from 251, occurred in situ at room temperature in the presence of Pd(PPh3)4 in MeCN, and obtained triphenylene (253) in 83 % yield [79]. 

The [2 + 2 + 2] cyclotrimerization of alkynes and its analogous arynes [134] leads directly to aromatic hydrocarbons and can be considered as special cases of [2 + 2 + 2] cycloaddition reactions of unsaturated compounds [135, 136]. Especially the catalyzed cyclotrimerization reactions are often highly regio- and stereoselective and have been established as valuable methods for the syntheses of highly substituted benzenes, biphenylenes, triphenylenes, and in the approach towards natural products. 

The first example of a transition metal-catalyzed cycUzation of arynes was reported in 1998 [112], when benzyne generated from o-(trimethylsilyl)phenyl triflate was shown to undergo cyclotrimerization in the presence of a catalytic amount of Pd(PPh3)4 to afford triphenylene (208) (Scheme 12.60). 

Pena D, P6rez D, Guitian E, Castedo L (1999) Synthesis of hexahenzotriphenylene and other strained polycyclic aromatic hydrocarbons by palladium-catalyzed cyclotrimerization of arynes. Org Lett 1 1555-1557. doi 10.1021/ol990864t... 

Polycyclic Arenes. Trimethylsilylphenyl triflates have found widespread use as benzyne precursors in the preparation of polycyclic arenes. Triphenylenes are made via paUadium-catalyzed [2 + 2 + 2] cyclotrimerization of arynes, by paUadium-catalyzed annulation of the aryne and 2-halobiaryls, or via carbopalladation/carbocycUzation of arynes with substituted iodobenzenes (eq 2). All three approaches furnish substituted triphenylenes in high reported yields. Substituted phenanthrenes or naphthalenes are similarly prepared using 2-(trimethylsilyl) phenyl triflate as an aryne precursor. Treatment of the reagent with fluoride, a palladium catalyst, and a deactivated alkene, allyl halide, or internal aIk5Tie provides 9-substituted or 9,... 

Finally, transition metal-catalyzed reactions of arynes have been explored as a useful method for the construction of a wide variety of carbo- and heteocycles. These reactions include cyclotrimerization of arynes, cocyclization of arynes with alkynes or alkenes, and carbopaUadation of arynes with Pd-complexes. Moreover, some insertion reactions of arynes into a-bonds are also catalyzed by metal complexes. 

The first metal-catalyzed reaction of arynes was described by Guitian in the late 1990s consisting in the cyclotrimerization of benzyne to yield triphenylene 100 (Scheme 12.51) [89]. These and other authors have extended this process to the trimerization of a variety of arynes, leading to polycyclic aromatic hydrocarbons (PAHs). 

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