Chlorobenzene Diels-Alder

For the microwave-assisted experiments, both solvents were replaced by 1,2-dichlorobenzene, as it couples very effectively with microwaves (loss-tangent (tan 5) at 20 °C 1,2-dichlorobenzene 0.280 as compared to 0.101 for chlorobenzene). Diels-Alder reactions of 3-methoxy or 3-phenyl pyrazinones with DMAD were performed at a pre-selected maximum temperature of 200 °C, whereas the intramolecular reaction of alkyne tethered pyrazinone required a higher temperature (220 °C). The yields obtained under microwave irradiation are comparable with those obtained under conventional conditions, while for the dihydrofuropyridinone the yield was improved from... 

As in the case of the solution-phase protocol, Diels-Alder reactions of the polymer-bound pyrazinones la,b were carried out in refluxing chlorobenzene (132 °C) and it required 1-2 days to drive these reactions to the completion (Scheme 44). Intramolecular cycloaddition of pyrazinone Ic was carried out in refluxing bromobenzene (bp 156 °C). Microwave-assisted cycloadditions of these substrates were performed in 1,2-dichlorobenzene at 220 °C and in significantly shorter reaction times (10-40 min). The product distribu-... 

Inter- and intramolecular hetero-Diels-Alder cycloaddition reactions in a series of functionalized 2-(lH)-pyrazinones have been studied in detail by the groups of Van der Eycken and Kappe (Scheme 6.95) [195-197]. In the intramolecular series, cycloaddition of alkenyl-tethered 2-(lH)-pyrazinones required 1-2 days under conventional thermal conditions involving chlorobenzene as solvent under reflux conditions (132 °C). Switching to 1,2-dichloroethane doped with the ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) and sealed-vessel microwave technology, the same transformations were completed within 8-18 min at a reaction temperature of 190 °C (Scheme 6.95 a) [195]. Without isolating the primary imidoyl chloride cycloadducts, rapid hydrolysis was achieved by the addition of small amounts of water and subjecting the reaction mixture to further microwave irradia-... 

A general hetero-Diels-Alder cycloaddition of fulvenes with azadienes to furnish tetrahydro-[l]pyrindines has been described by Hong and coworkers (Scheme 6.241 see also Scheme 6.92) [424]. A solution of the azadiene and fulvene (1.2 equivalents) precursors in chlorobenzene was heated under open-vessel microwave irradiation for 30 min at 125 °C to provide the target compounds in excellent yields and with exclusive regio- and diastereoselectivity. Performing the reactions under conventional conditions or under microwave irradiation in different solvents provided significantly reduced yields. 

A versatile new and general method was developed for the synthesis of six-membered 1,3-heterocycles. In comparison with the general reaction conditions of retrodiene reactions, a very mild retro Diels-Alder (RDA) decomposition was found to occur when the norbornene-d/eAro- or -diendo-fused dihydrooxazinone 474 was heated at melting temperature or refluxed in different solvents (e.g., chlorobenzene). Cyclopentadiene splitt off and the 2-aryl-6//-l,3-oxazin-6-ones 475, earlier unknown representatives of the simple 1,3-oxazines, were obtained (84S345, 84T2385). 

The use of phenyl vinyl sulfoxide as an acetylenic synthon in Diels-Alder reactions was reported in 1978 [525]. By heating phenyl vinyl sulfoxide with anthracene in chlorobenzene at 130°C for 120h, dibenzobarrelene was obtained in an 83% yield through elimination of phcnylsulfinic acid (see Section 3.1) from the primary cycloadduct. 

Breton and Martin <2002JOC6699, 20010L3185> reported the cycloaddition of 3-methyl-l,3,5-triazabicy-clo[3.2.0]hept-6-ene-2,4-dione 63 with a number of different dienes leading to the formation of [4+2] cycloaddition products. Most of the Diels-Alder cycloadditions of 63 were carried out in either benzene or chlorobenzene at a temperature of 100-150 °C. 

I highly reactive triple bond of benzyne is a powerful dienophile. Predict the product of the Diels-Alder reaction of benzyne (from chlorobenzene and NaOH, heated) with cyclopentadiene. 

When anthracene is added to the reaction of chlorobenzene with concentrated NaOH at 350 °C, an interesting Diels-Alder adduct of formula C20H14 results. The proton NMR spectrum of the product shows a singlet of area 2 around 8 3 and a broad singlet of area 12 around 8 7. Propose a structure for the product, and explain why one of the aromatic rings of anthracene reacted as a diene. 

Dieh-Alder reactions with benzyne. Shepard has recently demonstrated that benzyne generated from chlorobenzene and LiTMP undergoes expected Diels-Alder cycloadditions with reactive dienes. The reaction with furane itself fails because of a base-promoted side reaction. 

Styrenes may give Diels-Alder adducts with arynes, the exo-cyclic double bond being part of the diene moiety Yields are generally rather low. The competition between [4+2] cycloaddition and Michael addition of benzyne (generated from chlorobenzene and... 

The hetero Diels-Alder reaction of a series of functionalized 2(li-f)-pyrazinones was studied in detail by Van der Eycken et al. [58, 65]. For example, in a series of intramolecular cycioadditions of alkenyl-tethered 2(li-f)-pyrazinones 27 the reaction required 1-2 days under conventional thermal conditions (chlorobenzene, reflux, 132 °C) whereas use of 1,2-dichloroethane doped with the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (bmimPFe) and use of micro-waves up to a temperature of 190 °C (sealed vessels) enabled the same transformations to be completed within 8-15 min. The primary imidoyl chloride cycloadducts were not isolated, but were rapidly hydrolyzed under the action of microwaves by addition of small amounts of water (130 °C, 5 min). The overall yields of 28 were in the same range as reported for the conventional thermal procedures (Scheme 11.8) [58]. 

In 1953, Robert s experiments on the conversion of C-labeled chlorobenzene with KNH2 into aniline gave strong support to the intermediacy of ortho-benzyne in this and related reactions. Additional direct evidence for the existence of ortho-benzyne was provided by the observation of its IR spectrum, sohd-state dipolar NMR spectrum, and NMR in a molecular container, and by UV photoelectron spectroscopy. Even at low temperatures, arynes are extraordinary reactive. The reactions of arynes can be divided into three groups (i) pericyclic reactions, (ii) nucleophilic additions, and (iii) transition-metal catalyzed reactions. The pericyclic reactions can be divided into several categories such as Diels-Alder reactions, [2-f2] cycloadditions, 1,3- and l,4-dipolar cycloadditions, and the ene reactions. Arynes react with practically aU kinds of nucleophiles. More recently, the transition-metal catalyzed reactions of arynes have been studied, in particular those involving palladium. 

While preparing benzonorbornadienes by the Diels-Alder cycloaddition of substituted benzyne intermediates with furan. Caster and coworkers discovered significantly differentregiochemistries be tween bromobenzene 121 and chlorobenzene 124 in the n-BuIi induced metallation step (Schemes 12.40 and 12.41) [72]. In the case of bromobenzene 121, benzyne intermediate 122 was generated via bromine-Uthium exchange, followed by elimination of UF trapping by furan then afforded 6-fluoro-9-oxabenzonorbornadiene (123). In contrast, aryne 125 was produced... 

Benzyne, from chlorobenzene and sodamide, and A -methyl-2-pyridone give 3-phenyl-l-methyl-2-pyridone in 5.4% yield, together with a small amount of l,r-dimethyl-2,2 -bipyridyl-6,6 -dione (Xn-709). ° 2-Pyridone undergoes N-and 0-arylation in low yield when treated with benzyne prepared from diazotized anthranilic acid. ° A small amount of acridone is formed also. However, A-methyl-2-pyridone and the methyl-l-methyl-2-pyridones react with benzyne from anthranihc acid to form the Diels-Alder adducts (XII-710). ... 

In their work on aureolic acid antibiotic, Franck and co-workers examined the Diels-Alder reaction of the quinone methide derived from 26 with sugar dienophile 27 (Scheme 4). Heating of 26 in a sealed tube for 3 days in chlorobenzene afforded cycloadducts 28 and 29 in a 4 1 ratio in 71% yield. The major product has the 5-configuration at C-3 and results from the addition of the diene to the si face of the dienophile, in the endo mode, as shown below (76). 

Diels-Alder addition of tetrachlorocyclopentadiene dimethylketal to endo-5-norbornene carboxylic acid produces (459). Ketal cleavage (H2SO4), cheletropic loss of CO (reflux in o-dichloro benzene), and aromatization (bromine in hot chlorobenzene) affords the endo-acid (460 X = Cl) which can be dechlorinated by reaction with Ni-Al alloy and alkali to give (460 X = H). The clean retention of stereochemistry in reaction sequence is suggested to be of value in the general synthesis of alicyclic-substituted benzonorbornenes the methyl ester of (460 X = H) can likewise be prepared without epimerization. ... 

In the absence of radical initiators, cyclopentadiene and MA form a 1 1 Diels-Alder adduct, bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (see Chapter 4). The Jo-adduct formed below 170°C, undergoes isomerization above 170°C to the exo-adduct/ " Both the endo- and oxo-adducts undergo homopolymerization to yield polymer containing equimolar amounts of the two monomers/ " Copolymerization occurs in the presence of radical initiators at a temperature where the initiator has a short half-life. For example, heating molten adduct with 6.6 mol % crr-butylhydroperoxide for 1 h at 240°C gives 83% copolymer. Heating the exo-adduct with 10 mol % /-butyl peracetate in chlorobenzene for 1 h gives a 72% yield of copolymer. 

The intramolecular Diels-Alder reaction has featured in a number of elegant syntheses of natural products in the past decade, and this trend shows little sign of diminishing. A particularly pleasing illustration of this approach to synthesis is provided by the synthesis of ( )-aspidospermidine (79) by Magnus et al. whereby the key intermediate (80) was produced by way of intramolecular Diels-Alder reaction of the indole 2,3-quinodimethane (78), generated from treatment of the imine (76) with the mixed anhydride (77) in chlorobenzene at 140 °C. 

Annulated pyridines 112 or 113 were formed on heating of triazines 110 or 111 bearing at position 3 NH-(CH2) -C=CH, 0-(CH2) -C=CH or S-(CH2) -C=CH groups in chlorobenzene or diphenylether (Scheme 46) [23,24]. This transformation is an example of intramolecular Diels-Alder reaction of 1,2,4 triazines accomplished with nitrogen elimination. 

Remarkably, this complete regiocontrol was due to the sterical hindrance imposed by the chlorine substituent on the diyne 88 building block—and therefore the use of alkynyl chloride 88 turned out to be ideal for the regioselective assembly of the chlorobenzene moiety of sporolide B (94). The [2 + 2 + 2] cycloaddition product 91 was then transformed into the o-quinone 92 to prepare the second key step of this total synthesis, the thermally induced intramolecular Diels-Alder macrocyclization reaction (Scheme 7.20). 

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