Synthesis of Benzene Derivatives

To synthesize benzene derivatives with more than one substituent, we must always take into account the directing effects of each substituent. In a disubstituted benzene, for example, the directing effects indicate which substituent must be added to the ring first. 

For example, the Br group in p-bromonitrobenzene is an ortho, para director and the NO2 group is a meta director. Because the two substituents are para to each other, the ortho, para director must be introduced first when. synthesizing this compound from benzene. 

Because the two groups are para to each other, add the ortho, para director first. 

Pathway [1], in which bromination precedes nitration, yields the desired para product, whereas Pathway [2], in which nitration precedes bromination, yields the undesired meta isomer. 

This pathway does NOT form the desired product. 

---

A -Amino- and A-substituted amino-pyrroles readily undergo Diels-Alder additions and add to activated alkynes at room temperature. The resulting azanorbornadienes extrude A-aminonitrenes and this forms the basis of an unusual synthesis of benzene derivatives (81S753,81TL3347). It has been found that ethyl/3-phenylsulfonylpropiolate (135) is a superior dienophile to DMAD (Scheme 50). 

Benzene and cyclooctatetraene (COT) derivatives are formed by [2+2+2] and [2+2+2+2] cycloadditions of alkynes. At first the metallacyclopropene 107 and metallacyclopentadiene 108 are formed. Benzene and COT (106) are formed by reductive elimination of the metallacycloheptatriene 109 and the metallacyclononate-traene 110. Formation of benzene by the [2+2+2] cycloaddition of acetylene is catalysed by several transition metals. Synthesis of benzene derivatives from... 

Selective synthesis of benzene derivatives via partially intramolecular cyclic carbopalladation is considerably more complex than the corresponding all-intramolecular processes. As it is generally difficult to specify the cascade-initiation point in the Type Ha cyclization process, it would generally be the least selective path. A priori, the most favorable might be the intra-inter cascade cyclization process (Type lib), since both the point of initiation and the queuing order between the two alkynes is sharply differentiated by the fact that one is intramolecular, while the other is intermolecular. Still, in-... 

Synthesis of benzene derivatives. An acetoxy-1,3-diene (conveniently generated by healing an < ,/3-imsa urated aldehyde or ketone with isopropenyl acetate,... 

B.iv.b. Regioselective Synthesis of Benzene Derivatives via Pd-Catalyzed Cross-Coupling of 4-Halo-2-cyclobuten-l-ones. The Pd-catalyzed reaction of 4-chloro-2-cyclobuten-l-ones with alkenylzirconium derivatives or alkenyltins and heteroaryltins followed by thermolysis at 100 °C has regioselectively (—95%) produced multiply substituted benzenet" (Scheme 17) and heteroarene-fused benzene derivatives (Scheme 18), respectively. 

Cycloaddition of alkynes is an easy and efficient approach towards the synthesis of benzene derivatives [21]. However, fluorine-containing alkynes are rarely shown to undergo such reaction [22]. [RUj(CO)32], with phosphine or some phosphine derivative as additive, is able to cyclotrimer-ize the trifluoromethyl group substituted internal alkynes [23]. Particularly, when 2-(diphenylphosphino)benzonitrile (2-DPPBN) is used, the cyclotrimerized unsymmetrical benzene derivative forms in 77-92% yield with more than 98% regioselectivity depending upon the substituent in Ar... 

Reactions between two olefins or two alkynes are also possible, although less common. 1,6-Diynes are fascinating substrates they are often paired with a third alkyne moiety or activated olefin to produce a seven-membered ruthenacycle, as the ruthenacyclopentadiene intermediate cannot undergo /3-hydride elimination because there is no available hydrogen. This second intermediate likely undergoes direct reductive elimination to afford the observed product, a six-membered ring Yamamoto and co-workers have reported regioselective synthesis of benzene derivatives from this synthetic pathway (81). 

Cycloaddition. In recent years, [2+2+2] cycloadditions are no longer limited to the synthesis of benzene derivatives. Many cycloadditions of various carbon and heteroatoms component combinations have achieved great success. In 2005, Evans and co-workers developed an asymmetric [2-I-2-I-2] cycloaddition of enynes 9 with symmetrical and unsymmetrical alkynes 10 to give 5-6 fused products 11 and 12 in good yields and excellent ees (Scheme 5) (14). Under the optimized conditions, highly regio- and enantioselective products were obtained from the reaction of enynes with unsymmetrical alkynes. 

SYNTHESIS OF BENZENE DERIVATIVES ELECTROPHILIC AROMATIC SUBSTITUTION... 

Since the first reaction was discovered by Reppe and Schweckendiek [4], numerous transition metals have been used to promote alkyne [2 + 2 + 2] cycloadditions [1]. The majority of attention has focused on group 9 and 10 transition elements, including Co, Rh, Ni, and Pd. In comparison to these precedents, [2 + 2 + 2] alkyne cycloaddition reactions involving group 8 metals have been relatively neglected. However, over the past decade, there has been significant progress in efficient and selective [2 + 2 + 2] alkyne cycloadditions catalyzed by ruthenium. In this section we review the synthesis of benzene derivatives via alkyne [2 + 2 + 2] cycloaddition both stoichiometrically and catalytically. 

Li, J., Jiang, H. and Chen, M. (2001) CuCli-induced regiospecifical synthesis of benzene derivatives in the palladium-catalyzed cyclotrimerization of alkynes. Journal of Organic Chemistry, 66(10), 3627-3629. 

---