Benzyne derivatives

Benzyne formation and their reactions are not limited to simple benzene derivatives. Heterocyclic mole-ules can also be used for benzene reactions. One important use of benzyne derivatives is in the Diels-Alder caction (see sec. 11.4.A). When 3-bromo-2-methoxypyridine (394) was treated with EDA at -78°C, for. ample, lithium-hydrogen exchange occurred to give 395. Loss of LiBr led to benzyne (396), which reacted with furan to give the Diels-Alder product (397) in 74% yield.  

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Benzyne, which is generated in situ from 2-(trimethylsilyl)phenyl triflate and KF, acts as an alkyne congener in distannation in the presence of palladium-/ r/-alkyl isocyanide complex.157 A variety of substituted benzyne derivatives inserts into the Sn-Sn bond to give l,2-bis(stannyl)benzenes (Equation (59)). The reaction fails to occur in the presence of other palladium catalysts such as Pd(PPh3)4. 

TABLE 16.2. Calculated and Experimental Data for Some m-Benzyne Derivatives... 

The reaction of o-diiodobenzene with Ni(CO)4 gives a black compound of composition [NiC7H4I20]2 which is thought to be a benzyne derivative... 

Again, benzyne derivatives could be considered as reactive alkynes and we have studied the anionic cyclization reactions of functionalized vinyl- and aryllithiums to these intermediates. We have developed a useful methodology that gives rise to a wide range of regioselectively functionalized heterocycles161. For instance, 4-functionalized indoles 379 have been prepared from simple A-2-bromoallyl-2-fluoroanilines 378. Treatment of these... 

The reaction between benzyne derivatives and selenium analogues of Barton s thiopyridone esters provided a convenient entry into complex, fused benzo[3]selenophenes <2004JHC13, 2004ARK51>. For example, the generation of the benzyne 86 in the presence of selenoester 85 provided benzo[. ]seleno[2,3-. ]pyridine 87, presumably via a single electron transfer (SET) pathway (Equation 11). This methodology was examined utilizing a number of benzyne precursors (anthranilic acids, iodium triflates, and trimethysilyl triflates) and provided access to an impressive number of fused benzo[. ]selenophenes. 

Clark, A. E. Davidson, E. R. p-benzyne derivatives that have exceptionally small singlet-triplet gaps and even a triplet ground state, 7. Org. Chem. 2003, 68, 3387-3396. 

Stevens and Bisacchi have carefully examined the trailing of benzynes, generated fiom a number of aryl bromides and sodium amide in THF, with 1,1-dimethylethylene and report procedures which afford 6 6% yields of 1,1-dimethoxycyclobutenes, e.g. (131). These compounds are hydrolyzed quantitatively to the corresponding benzocyclobutenones (132). Excellent regioselectivity was obtained with unsym-metrical benzynes derived from methoxy substituted bromobenzenes due to the polarized nature of the benzyne intermediate. Steric effects also influence regioselectivity o-bromotoluene afforded a 3 1 mixture of 3-methyl- and 6-methyl-benzocyclobutene. 

N-AlkylaniUmes. Treatment ofbromobenzene substituted in the meta position by electron-attracting groups [OCH3, Cl, N(CH,)2] with sodium amide generates a benzyne derivative which reacts with a primary aliphatic amine to give the corresponding... 

The electrophilicity of benzyne (90) is 1.95 eV, a value that falls within the range of strong electrophiles in the w scale.102 This value, which is larger than that evaluated for acetylene (32), to = 0.54 eV, allows to explain the reactivity of the benzyne derivatives towards nucleophilic additions. The electrophilicity of the fused four-membered... 

The analysis of the local electrophilicity at the fused four-membered benzyne derivative 91 indicated that the strained substituent present on the C3 position breaks the symmetry of benzyne (90), and the Cl carbon atom becomes slightly more electrophilic than the C2 one. This result is in agreement with the regioselectivity observed in the nucleophilic additions to 91 (see Scheme 15). 

Grignard-based benzyne reactions typically produce numerous benzyne-derived by-products. For this reason, yields of benzonorbomadiene via this route are often moderate (-50%), as we also observed on large-scale. Fortunately, the by-products are higher in molecular weight, allowing purification based on boiling point. Additional removal of undesired products from the distilled cmde reaction extracts (typically >90% pure) was achieved in the dihydroxylation step with OSO4, which sequestered all benzonorbomadiene as crystalline analytically pure diol 4 (see Scheme 3.1 and Scheme 3.4). 

A new cathodic cyclodimerisation of 4-pyrones yields either (90) or (91) depending on conditions,88 2-Benzopyran-3-one has been isolated at low temperature and intercepted by NPM as the adduct (92) 88 high-pressure cycloaddition reactions of 2H-pyran-3-ones with a variety of dienophiles have been recorded.88 Cycloaddition reactions of furans and isobenzofurans continue to dominate this section. Dienophiles whose reactions with furan have been studied recently include phenylsulphonylpropadiene (giving predominantly the endo-adduct (93) 8b. benzynes (derived from aryloxazoli nesJ.8 and... 

To conclude this section, it is important to note that alkenes are not the only hydrocarbon dienophiles that are useful partners in the Diels-Alder reaction. Alkynes and even benzyne are quite useful. As a structure proof of an intermediate in Pandey s synthesis of epiboxidine, the methyl carbamate of pyrrole (34) reacted with dimethyl-2-butynoate (35),in the presence of aluminum chloride (see sec. 11.6.A for a discussion of Lewis acid catalysis) to give a 90% yield of azanorbomadiene (36). A benzyne derivative of pyridine was... 

Treatment of the bromoenaminones 250 with lithium diethylamide in ether-THF causes intramolecular cyclization to give the dihydroindoles 251, Scheme 67. Benzyne derivatives were assumed to be the reactive intermediates (78TL3817). 

Thiophene is generally considered the most aromatic of the five-membered heterocycles, hence its reluctance to function as a diene in cycloadditions. A detailed study of the reaction of thiophene with six common benzyne precursors showed that side reactions with intermediates en route to benzyne often dominate the reaction course. Best results were obtained with diphenyliodonium-2-carboxylate 294, which gave up to 30% yields of naphthalene, presumably mainly through intermediate 295. Other benzyne-derived products [benzo( )thiophene, 0.5% 2-phenylthiophene, trace diphenyl sulfide, trace 1- and 2-naphthyl phenyl sulfides, 9 and 6%, respectively o-(2-thienyl)biphenyl, 4%] bring the... 

The practice of using an insoluble polymer to isolate and kinetic-ally stabilize a reactive intermediate has been addressed in several reports, most commonly using DVB cross-linked polystyrene as a support. In these cases, the three dimensional structure of the polymer and rigidity of the polymer backbone diminish intramolecular reactivity between two sites on the same polymer bead. Physical constraints preclude any significant reaction between two different polymer beads. Similar, less dramatic reduced intramolecular reactivity has also been noted for reactive intermediates bound to linear polystyrene. For example, o-benzyne bound to linear polystyrene has been shown by Mazur to have enhanced stability relative to non-polymer-bound -benzyne (35). In this case, o-benzyne was generated by lead tetraacetate oxidation of a 2-aminobenzotriazole precursor, 1. Analysis of the reaction products after cleaving the benzyne derived products from the polymer by hydrolysis showed a 60% yield of aryl acetates was obtained (Equation 11). In contrast, the monomeric aryne forms only coupled products under similar conditions. Further comparisons of the reactivity of -benzyne bound to insoluble 2% or 20%... 

T. Hoye et al. were understandably surprised when a seemingly trivial oxidation of 7 took an unexpected course (Scheme 7.28). Instead of ketone 8 the tricyclic product 9 was obtained in 53% yield. The course of the events could be rationalized readily and pointed to the unprecedented cyclization of ketone 8 to give the benzyne derivative 10 in a [4-1-2] cycloaddition between a diyne and an yne moiety. In fact, this intramolecular cycloaddition turned out to be a viable route to generate arynes bearing electron-withdrawing substituents, a substitution pattern that is not always amenable to the standard methods for generating arynes. Thus, this surprising reaction broadens the scope of benzyne chemistry. 

Finally, several likely aryne precursors in this category fail. Neither thermolysis nor photolysis of the tosylhydrazone derivative 64 yields any benzyne-derived products.Instead, the rearranged benzoxazolone (65) forms and, like... 

The application of 1,2-dihaloarenes in organic synthesis has experienced long-term development. The most common application is the in situ generation of benzyne derivatives. However, using transition metal catalysts with 1,2-dihaloarenes as substrates offers more diversity for the outcome. 

The use of benzyne derivatives in intermolecular carbo-palladation processes has stood out as a powerful tool for the preparation of 1,2-functionalized arenes in the last decade. Since the pioneering work by Yamamoto in 2000 [34], which introduced arynes as reactive partners in palladium-catalyzed reactions, several groups have exploited the carbopallada-tion of benzyne in three-component couplings. In general, 2-(trimethylsilyl)phenyl triflate derivatives, in combination with a fluoride salt such as CsF, are used as benzyne precursors. 

The stabilization and isolation of both cyclobutadiene and benzyne derivatives were first achieved by their isolation as metal 7r-complexes because of academic interest. However, industrial processes such as the Ziegler-Natta olefin polymerization, the Wacker olefin oxidation of alcohols to aldehydes and ketones, and the hydroformylation of olefins, among others, have provided practical applications for achievements in metal i-complex chemistry. Still to be determined are the exact role of metal 7r-complexes in many vital biological functions and processes such as nitrogen fixation by plants. 

A furthCT report of isomerism and dynamic stereochemistry in vinylidene complexes [Os3H2(CO)9(C2R R )] has appeared. The isomers [Os3H(Et2PC=CH2)-(CO) l and [Os3H(CHCH)(PEt2)(CO)9] are both fluxional with easy movements of the unsatnrated ligands in processes related to those of the previously reported vinyl and benzyne derivatives, respectively. ... 

Tb 3 z-r] Pyrroles undergo Diels-Alder additions with benzyne derivatives of 2-naphthylamine result from rearrangement of the initial products . ... 

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