Enynes cross-benzannulation

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]. 

Intermolecular enyne-diyne cross-benzannulation offers a convenient synthetic method for cyclophanes. The cyclic enyne 213 reacted smoothly with 12-carbon-tethered cyclic diyne 214, and the meto-cyclophane having both 15- and 16-membered rings 215 was prepared in high yield (72 %) [65],... 

TABLE 4. Pd-Catalyzed Cross-Benzannulation Between 4-Snbstitnted Conjngated Enynes... 

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

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

Although a mechanism of the above palladium-catalyzed cross-benzannulation between conjugated enynes and diynes is not perfectly understood, the reaction may proceed via not a concerted mechanism but a stepwise mechanism [48]. 

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. ... 

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). 

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. 

SCHEME 14.10 Pd-catalyzed [4 + 2] cross-benzannulation reaction of two enynes. 

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

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. 

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],... 

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

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

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

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. 

Gevorgyan, V.,Tsuboya, N. and Yamamoto, Y. (2001) Synthesis of cyclophanes via an intermolecular Pd-catalyzed enyne-diyne cross-benzannulation approach. Journal of Organic Chemistry, 66(8), 2743-2746. 

The aryl bromide 40, prepared from cross-coupling between 1,2-dibromobenzene and (trimethylsilyl)acetylene, was converted to the corresponding arylzinc halide 41a and arylboronic acid 41b for subsequent coupling with the haloallenes 42 to produce the benzannulated enyne-allene 43 in -40% yield (Scheme 20.10) [38]. Desilylation with tetrabutylammonium fluoride (TBAF) then afforded 44 in 67% yield. 

The use of l-iodo-9-fluorenone (59) for cross-coupling with phenylacetylene produced 60, which on treatment with 51 gave the benzannulated enyne-allenes 61 (Scheme 20.14) [43], Thermolysis of 61 in 1,4-CHD at 75 °C promoted the Myers-Saito cyclization reaction, leading to 63 in excellent yields. Again, the benzylic radical center in 62 is a stabilized triarylmethyl radical. 

A palladium-catalyzed intramolecular benzannulation of bis-enynes 1135 proceeds chemoselectively to afford dihydroisocoumarins 1136 (Equation 441) <2002JOC2653>. A reaction sequence involving ruthenium-catalyzed yne-ene cross-metathesis of a polystyrene supported undecynoic acid ester followed by a Diels-Alder cycloaddition reaction with DMAD provides the basis for a combinatorial approach to dihydroisocoumarins featuring a variety of side chains at C-6 and C-8 <1999SL1879>. 

Another type of benzannulation, which might be related to the benzannulation of conjugated enynes, is the Pd-catalyzed cyclotrimerization of 1,3-diynes (Scheme 1,3-Diynes cyclotrimerize in the presence of a Pd catalyst to give 1,3.5-trisubstituted benzene derivatives. In this reaction, too, the regioselectivity is perfectly controlled as shown in Scheme 4, and other products were never isolated. The reaction of various diynes is summarized in Table 7. Some functional groups such as olefins and ether linkages may be present in the side chain. An example for the cross-cyclotrimerization of a diyne and an aUcyne has also been reported (Scheme... 

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... 

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