Benzannulation of Enyne with Diyne

SCHEME 14.17 Scope of the Pd-catalyzed [4 + 2] cross-benzannulation reaction of enyne with diyne. 

TABLE 14.3 Pd-Catalyzed [4 + 2] cross-Benzannulation Reaction of 2-Methylbut-l-en-3-yne with Unsymmetrically Substituted Diynes 

The reactivity trend of enynes for cross-benzanulation reaction remains consistent to that of the palladium-catalyzed homo-benzannulation of two enynes. However, in this case, the scope is expanded to 1,4-disubstituted and 1,2,4-trisubstituted substrates. 

SCHEME 14.19 Sonogashira cross-coupling reaction followed by intramolecular cross-benzannulation reaction. 

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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. 

Two possible approaches were shown for the Sonogashira cross-coupling/ benzannulation of enyne with diyne cascade transformation (Scheme 14.19) [11a]. Accordingly, three-component coupling between dihalide 41 and two molecules of terminal diyne produced phenanthren-9(10//)-one derivatives 43 with modest yields under Sonogashira cross-coupling conditions (path A). Incorporation of two different substituents to the final product 46 was achieved via a stepwise addition of terminal alkynes (path B). 

SCHEME 14.24 Synthesis of aryl ethers via Pd-catalyzed cross-benzannulation of enynes with diynes. 

SCHEME 14 JO S5mthesis of cyclophanes via Pd-catalyzed [4 -I- 2] cross-benzannulation of enynes with diyne. 

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. 

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],... 

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). 

Also, the [4+2] benzannulation of enyne 154 with diyne 155 proceeds chemo- and regioselectively to afford 156 [66], A similar reaction of enyne silyl enol ether 157 with the diyne offers a good synthetic route to polysubstituted phenols 159 via 158 [67]. In this reaction enol silyl ethers having the (E) configuration as shown in 157 give satisfactory results. 

D. [4 + 2] ANNULATION OF CONJUGATED ENYNES WITH DIYNES (CROSS-BENZANNULATION)... 

TABLE 9. Pd-Catalyzed Cross-Benzannulation of Conjugated Enynes with Diynes (2)... 

Different types of cyclophanes, such as ortho-, meta-, or paracyclophanes, were obtained via the intermolecular Pd-catalyzed [4 - - 2] cross-benzannulation of cyclic enynes with diynes [2Id]. For example, cyclophane-type compound 78, containing both meta- and orthocyclophane motifs, was synthesized upon reaction of enyne 79 and diyne 80 (Scheme 14.30). 

Scheme 2.75 Palladium-catalyzed cross-benzannulation of enynes 2.218 with diynes 2.219.

In Pd(0)-catalyzed reactions, the LAs and Bronsted bases not only promote the E/Z isomerization, but also accelerate the [4-1-2]-benzannulation of enyne. This was tested in the reaction of a series of differently substituted enynes 2.246 with diynes 2.247 in the presence of either acids or bases (Scheme 2.82) [11]. 

Scheme 2.82 Base-promoted Pd-catalyzed [4-1-2] benzannulation of enynes 2.246 with diynes 2.247. O-TBS is protecting group, 0-Si(CH3)2 C4H9.

Gevorgyan, V., Takeda, A., Homma, M., Sadayori, N., Radhakrishnan, U. and Yamamoto, Y. (1999) Palladium-catalyzed [4-1-2] cross-benzannulation reaction of conjugated enynes with diynes and triynes. Journal of the American Chemical Society, 121(27), 6391-6402. 

The aniline derivative 208 was obtained by cross-benzannulation of the amino-enyne 207 with dodeca-5,7-diyne (50) [64]. Cross-benzannulation of the 1,4-disubstituted enyne 209 with fte diyne 50 afforded the 1,2,3,4-tetrasubstituted benzene 210 [63]. Pentasubstituted benzene 212 can be synthesized by the coupling of the trisubstituted l-buten-3-yne 211 with the diyne 50 [63]. 

The Pd(0)-catalysed 4 -i- 2-cross-benzannulations of conjugated enynes (167) with diynes (166) and triynes yield substituted benzene derivatives (168) (Scheme 64). " Monosubstituted conjugated enynes readily undergo 4 - - 2-homodimerization in the presence of Pd catalyst to produce 4,o - and 2,6-disubstituted styrenes. ... 

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... 

The synthesis of derivatives of phenol and aniline via Pd-catalyzed benzannulation of substituted enynes and diynes has been described. For example, phenol derivatives 2.224, 2.226, and 2.229 were prepared by the benzannulation with alkoxyenynes 2.222 and 2.225 or... 

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