Cyclohexadiene derivatives

Beside the polymerization routes of 1,3-cyclohexadiene derivatives repetitive Diels-Alder polyadditions were widely used to prepare arylated PPPs. Stille et al. developed a set of suitable monomers (1,4-diethynylbenzene and 1,4-phenyl-ene-bis(triphenylcyclopentadienone) derivatives) to generate phenylated PPPs (e.g. 17) with molecular weights of 20,000-100,000 [31]. Unfortunately, the repetitive polyadditon does not proceed regioselectively polymers containing para-as well as mefa-phenylene units within the main chain skeleton are formed. 

This chapter covers reactions in which coordination of a transition metal to the ir-system of an arene ring activates the ring toward addition of nucleophiles, to give V-cyclohexadienyl-metal complexes (1 Scheme 1). If an electronegative atom is present in the ipso position, elimination of that atom (X in 1) leads to nucleophilic aromatic substitution (path a). Reaction of the intermediate with an electrophile (E+) can give disubstituted 1,3-cyclohexadiene derivatives (path b). If a hydrogen occupies the ipso posi-... 

The /-/ -bcnzcncmolybdcnum tricarbonyl complex 187 also suffered nucleophilic addition of 2-lithio-l,3-dithiane or its 2-methyl derivative at — 78 °C to give the ry -cyclohexadienyl anionic complexes 188, which were trapped with allylic bromides to yield, after CO insertion under CO pressure, trans-5,6-disubstituted 1,3-cyclohexadiene derivatives 189 (Scheme 55)253. Analogous reactions with [( 6-benzene)Cr(CO)3] give directly the corresponding cyclohexadiene in which the CO has been inserted in the allyl group. 

The reaction of electron-poor butadienes with enamines can afford the corresponding benzenes by treatment of the initial 1,3-cyclohexadiene derivatives with some oxidants or by heating96. An example is the preparation of sulfonyl benzenes 186 from disulfonyl dienes 183 and enamines 184 giving adduct 185, which then aromatizes (equation 38)97,98. The presence of an additional unsaturation like in trimethylsilyl... 

Under certain conditions, apparently when the Cr(CO)3 unit is spontaneously displaced from the product by a weak donor ligand (solvent), the simple addition product (1,3-cyclohexadiene derivative) can be the major product (equation 107). ... 

Roberts et al. in the early 90s reported that 1,3-cyclohexadiene derivatives such as 24 and diphenylketene undergo [2 + 2] and [4 + 2] cycloaddition reactions simultaneously to afford mixtures of adducts 25 and 26 (Scheme 11) (1992JCS(P1)1617, 1990JCS(P1)2613). Notably, in the case of R = H, the ratio is 56 44, whereas R = F afforded the [4 + 2] cycloadduct as the major product (1990JCS(P1)2613). Heating of the [4 + 2] cycloadduct causes partial isomerization to afford the [2 + 2] cycloadduct, indicating that the [4 + 2] cycloadduct is a kinetic product while [2 + 2] adduct is thermodynamically more stable (1992JCS(P1)1617). 

A series of 1,3-cyclohexadiene derivatives have also been obtained by reduction of chloro, aryloxides of niobium and tantalum." These compounds are potential intermediates within the catalytic cycle of arene hydrogenation. Structural smdies of derivatives such as [M(OAr)3( /" -C6H8)] (M = Nb, Ta OAr = OC6H3Pi -2,6) show a metallanorbornene bonding picture. These compounds are not only precursors for arene hydrogenation, but will also catalyse both disproportionation and hydrogenation of 1,3-cyclohexadiene." ... 

Category A 1,3-Cyclohexadiene-Forming Reactions. Diels-Alder reactions of thiophene 1,1-dioxides and their derivatives usually lead to 1,3-cyclohexadiene derivatives with spontaneous loss of sulfur dioxide from the initial adducts. This type of reaction has been most extensively examined with tetrachlorothiophene 1,1-dioxide. A large variety of olefinic compounds reacted with tetrachlorothiophene 1,1-dioxide to form l,2,3,4-tetrachloro-l,3-cyclohexadiene derivatives... 

Scheme 83 Preparation of 1,3-cyclohexadiene derivatives from 3,4-dichlorothiophene 1,1-dioxide by [4+2] Diels-Alder cycloaddition [89]...

Dichlorothiophene 1,1-dioxide can also react with olefinic compounds affording 1,3-cyclohexadiene derivatives in good yields (Scheme 83) [89]. 

Cycloadditions constitute a remarkable tool for the synthesis of 1,3-cyclohexadiene derivatives and related heterocyclic compounds. Surprisingly, no cyclotrimerization of alkynes (Reppe reaction) has been reported to date with NHC-Ni complexes. 

Methyl 6-hydroxy-3-methylhexanoate is our 1,6-difunctional target molecule. Obvious precursors are cyclohexene and cyclohexadiene derivatives (section 1.14). Another possible starting material, namely citronellal, originates from the "magic box of readily available natural products (C.G. Overberger, 1967, 1968 E.J. Corey, 1968D R.D. Clark, 1976). 

The cyclization of the enediynes 110 in AcOH gives the cyclohexadiene derivative 114. The reaction starts by the insertion of the triple bond into Pd—H to give 111, followed by tandem insertion of the triple bond and two double bonds to yield the triene system 113, which is cyclized to give the cyclohexadiene system 114. Another possibility is the direct formation of 114 from 112 by endo-rype. insertion of an exo-methylene double bond[53]. The appropriately structured triyne 115 undergoes Pd-catalyzed cyclization to form an aromatic ring 116 in boiling MeCN, by repeating the intramolecular insertion three times. In this cyclization too, addition of AcOH (5 mol%) is essential to start the reaction[54]. 

The cyclohexadiene derivative 130 was obtained by the co-cyclization of DMAD with strained alkenes such as norbornene catalyzed by 75[63], However, the linear 2 1 adduct 131 of an alkene and DMAD was obtained selectively using bis(maleic anhydride)(norbornene)palladium (124)[64] as a cat-alyst[65], A similar reaction of allyl alcohol with DMAD is catalyzed by the catalyst 123 to give the linear adducts 132 and 133[66], Reaction of a vinyl ether with DMAD gives the cyclopentene derivatives 134 and 135 as 2 I adducts, and a cyclooctadiene derivative, although the selectivity is not high[67]. 

Acetylene like ethylene is a poor dienophile but alkynes that bear C=0 or C=N substituents react readily with dienes A cyclohexadiene derivative is the product... 

Reduction of arenes by catalytic hydrogenation was described m Section 114 A dif ferent method using Group I metals as reducing agents which gives 1 4 cyclohexadiene derivatives will be presented m Section 1111 Electrophilic aromatic substitution is the most important reaction type exhibited by benzene and its derivatives and constitutes the entire subject matter of Chapter 12... 

If the Lewis base ( Y ) had acted as a nucleophile and bonded to carbon the prod uct would have been a nonaromatic cyclohexadiene derivative Addition and substitution products arise by alternative reaction paths of a cyclohexadienyl cation Substitution occurs preferentially because there is a substantial driving force favoring rearomatization Figure 12 1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution For electrophilic aromatic substitution reactions to... 

A useful and possibly more general alternative to the Lwowski synthesis- of 1,3-diphenylisoindoles involves condensation of a l,2-dibenzoyl-l,4-cyclohexadiene (e.g., 55) with ammonia or a primary amine. Cyclohexadiene derivatives of this type are easily prepared by Riels-Alder addition of a 1,3-diene to dibenzoylacetylene, and these adducts lead directly, and in high yield, to the corresponding isoindoles (56). The reaction is closely related to the well-known synthesis of pyrroles by condensation of 1,4-diketones with ammonia. 4,7-Dihydro- and 4,5,6,7-tetrahydroisoindoles (57 and 58) have been... 

Existing substituent groups such as CH3, OCH3, and +N(CH3)3 exert a directive effect, often resulting in a major amount of the meta substitution product.323 The intermediate adducts can be converted to cyclohexadiene derivatives if the adduct is protonolyzed.324... 

With an effective strategy for construction of the diazofluorene established, we set out to prepare the coupling partners required for synthesis of (—)-kinamycin F (6). The synthesis of the enone 117 began with meta-cresol (128, Scheme 3.23). Silylation formed the silyl ether 119 in nearly quantitative yield. Birch reduction of the silyl ether 119 formed the cyclohexadiene derivative 129 in excellent yield. Asymmetric dihydroxylation [52] of 129 occurred regioselectively to afford the... 

Treatment of trans,trans-2,6-ociddiene (122) with deuteriated formic acid HCO2D in the presence of deuteriosulphuric acid gave the cyclized formate ester 123. A concerted mechanism (equation 63) was proposed for this reaction73. The stereospecific ring-closure of the 1,4-cyclohexadiene derivative 124 in acetic anhydride/perchloric acid affords the octalin 125, which was isolated as the diacetate 126 (equation 64)74. 

Beyond dimerization and oligomerization, [2 + 2]- and [4+ 2]-cycloadditions with conjugated dienes and styrenes and the addition of nucleophiles are typical reactions of strained cyclic allenes. These transformations have been studied most thoroughly with 1,2-cyclohexadiene (6) and its derivatives [1, 2]. Concerning the cycloadditions, a theoretical study had the surprising result that even the [4+ 2]-cycloadditions should proceed in two steps via a diradical intermediate [9]. In the case of nucleophiles, the sites of attack at several 1,2-cyclohexadiene derivatives having an... 

Dauben and coworkers produced a number of lovely examples of the reaction in the course of their studies of the photochemistry of large-ring (Cs-Cn) cyclic trienes, many of which were produced by photochemical electrocycloreversion of the isomeric annulated cyclohexadiene derivatives (cf Reference 172 and references cited therein). Two examples... 

The polysubstituted benzenes 291 and 292 were also obtained by protonation of the cyclohexadiene derivatives 287 -289 (equation 101)155. The migration of the propynyl... 

Cyclohexadiene derivatives are less reactive than butadiene derivatives, thus only a few examples of cycloadditions with these compoimds are known (Figure 4.3) [37 0]. The cyclohexadiene bicychc derivative 32 was synthesized by rhodium-catalyzed reaction of toluene with tert-butyldiazoacetate and cycloadds in about 40% yield to Cjq [39]. The product has anti-cyclopropane orientation relative to the entering dienophile Cjq. Valence isomerization of 33 (Scheme 4.4) leads to the cyclobutene-fused cyclohexene 35 that adds in good yields (50%) at moderate temperatures (110 °C) to Cjq [40]. The reaction of with the electron-deficient cyclohexene 34 is also possible in moderate yields [38]. 

Addition of a cyanohydrin acetal anion to [(benzene)Cr(CO)3] followed by reaction with allyl bromide produces the cyclohexadiene derivative (73) in 94% yield, which undergoes a Diels-Alder reaction rapidly to give a tricyclic framework (74). After quenching with methyl iodide and disassembling of the cyanohydrin group, the diketone (75) is obtained in 50% yield overall (equation 51).125 These products are obviously interesting as potential intermediates for synthesis. 

Cathodic reduction of arylsilanes in methylamine using LiCl as a supporting electrolyte in an undivided cell gives 1,4-cyclohexadiene derivatives. The reaction seems to proceed in a manner similar to the Birch-type reduction. The cathodic reduction in a divided cell provides desilylation products (equation 53)68. 

Birch reductions of monosubstituted arenes yield 1,4-cyclohexadiene derivatives in which the alkyl group is a substituent on the double bond. With p-xylene, both methyl groups are double-bond substituents in the product. 

In all cases, 4-acetyl-5-Z-8-methyl-ll-oxatricyclo[6.3.0.01,4]undeca-2,5-di-enes (Z = OMe, F, CH3, CF3), resulting from syn addition, were the predominant photoproducts, as determined by direct NMR analysis. Following thermal treatment, the cyclooctatriene and/or cyclohexadiene derivatives were then isolated in 60-70% yield in the ratios shown in Scheme 21. With 2-methyl, 2-methoxy, and 2-trifluoromethyl substitution, the reaction is 100% regioselective syn, addition of the remote double bond occurring only at the 3,4-positions of the benzene ring, not the 4,5. The 2-fluoro derivative alone provides both anti and syn regioisomers in a 15 85 ratio. The 2-cyano derivative did not react. The authors surmised that the... 

Prior to the work of Cheng et al. Rubin et al. reported a similar [4 + 4] pho-tocyclization reaction [299]. Rubin has shown that a cyclohexadiene derivative underwent a very facile photochemically promoted rearrangement to the stable bridged bisfulleroid 198 (Scheme 76). This process occurs via the initial [4 + 4] photoadduct (not observed), which undergoes a thermally allowed [2 + 2 + 2] cycloreversion to afford a bis-methano[12]annulene structure 198. Alternatively, compound 198 can be obtained by photolysis of the allylic alcohol 197 under reflux and acidic conditions in good yields. The allylic alcohol is obtained by acidic... 

Aromatic nucleophlic substitution with stabilized carbanions is possible, and nucleophilic substitution products and cyclohexadiene derivatives are preparable. 

The retrosynthetic approach to welwitindolinone A isonitrile (6) used by the Wood group is shown in Scheme 33. After recognition of the possibility of deriving the vinyl isonitrile fragment from a ketone, the disconnection of 6 to 140 was proposed. A literature report of a samarium (II) iodide-mediated reductive coupling of acrylates with isocyanates to give amides, which could be expected to lead to a new spirooxindole synthesis, prompted the disconnection of 140 to 141. This compound was to be obtained from the readily available cyclohexadiene derivative 143, by way of bicyclic ketone 142. 

However, not only the protonating ability of IIGeCh or systems derived from it determine the addition to aromatic carbon-carbon bonds, in contrast to the behavior of other HX acids. The specific features of HGeCl3 are probably manifested at the step of the cyclohexadiene derivative formation. Energy is obviously lost during the conversion from a-complex to cyclohexadiene. The formation of the cyclohexadiene-GeCl2 molecular complex (the GeCl2 present in the reaction mixture is a result of a well-known reaction, cf. Section III) is likely to be responsible for the equilibrium shift in the direction of the cyclohexadiene. It is likely that application of some other compounds which provide such shift by complexation with cyclohexadiene will enhance the addition of other HX acids to aromatic double bonds. 

Reactions of 32a with acyclic dienes (butadiene and piperylene) yielded the cyclohexadienes derived from desulfinylation of the resulting adducts, precluding the deduction of any information about the stereochemical course of these reactions [45]. From the results of the reaction of racemic sulfoxide 34 with the acyclic diene 35, Alexandre et al. [48] were able to isolate and characterize bicy-clic adduct 36 as the only adduct because its desulfinylation required 30 min in CH2C12 under reflux (Scheme 17). This result proved that the exo-selectivity of these reactions with acyclic dienes is much higher than that with cyclic dienes. Moreover, this paper shows that the reactivity of 3-sulfinyl acrylates is lower than that of the 2-sulfinyl derivatives, because the former are not able to react with 35. 

Thus, according to Scheme 28, (-)-shikimic acid 169 was converted to cyclohexadiene derivative 170 via esterification of carboxyl group, protection of the m-disposed hydroxyls, and elimination of the remaining carbinol moiety. Catalytic dihydroxylation of 170 gave unsaturated esters 171 and 172 as a separable 1 1 mixture. The 5,5a-unsaturated isomer 171 was finally elaborated into the desired (-)-MK7607 (174) via simple protection-reduction-deprotection sequence. 

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