Unsubstituted 1,2-Cyclohexadiene

An enormous amount of work has been dedicated to six-membered cyclic allenes. This justifies the organization of the subject in several subsections unsubstituted 1,2-cyclohexadiene (6) (6.3.1), substituted 1,2-cyclohexadienes (6.3.2), bridged and annulated 1,2-cyclohexadienes (6.3.3), 1,2,4-cyclohexatriene (162), 3d2-1 /-/-naphthalene (221) and their derivatives (6.3.4), heterocyclic derivatives of 1,2,4-cyclohexatriene and 3 d 2 -1H - napht h a I cn c (6.3.5) and heterocyclic derivatives of 1,2-cyclohexa-diene (6.3.6). 

The reversal of the thermal decomposition of 6 to ethylene and vinylacetylene cannot be utilized to generate 6, since, according to a quantum-chemical analysis, the reaction is slightly endergonic and requires a large free activation enthalpy (0.9 and 42 kcal mol-1, respectively) [59]. The intramolecular variant of this process as well as the addition of typical dienophiles of the normal Diels-Alder reaction to divinylace-tylenes will be discussed at the end of Section 6.3.3. 

Moore and Moser [44] obtained 38 and the tetramers 39 of 6 as products of the reaction of 35 with methyllithium in diethyl ether. The best yield of 38 (55%) resulted at 35 °C, whereas only a trace of 38 was observed at -80 °C, at which temper- 

Generating 6 from 6,6-dibromobicydo[3.1.0]hexane (35) with methyllithium in the presence of styrene, Moore and Moser [55] observed the first [2 + 2]-cycloaddi-tions of 6. Bottini et al. extended the variety of compounds able to trap 6 to 1,3-cyclo-hexadiene [54, 60], furan, 2-methyl furan, 1,3-cyclopentadiene and methyl-substituted 1,3-butadienes [54], In all these reactions, the dimer 38 of 6 is a byproduct or, as in the case of the less reactive trapping agents, even the main product. Hence it is advisable to use a reaction partner of 6, if it is a liquid, as the solvent. 

The cycloadditions of 1-substituted 1,2-cyclohexadienes and among them their dimerization are of interest because of the position selectivity. Does the reaction occur at the substituted or the unsubstituted ethylene subunit For that question to be answered, 1-methyl- (74), 1-phenyl- (75), 1-cyclopropyl- (76), l-(3-phenylpropyl)-(77) and l-trimethylsilyl-l,2-cyclohexadiene (79) were generated from the corresponding 1-substituted 6,6-dibromobicyclo[3.1.0]hexanes with methyllithium. Several of these dibromides are thermolabile, which particularly applies to the phenyl (93) [76] and the cydopropyl derivative [70], In those cases, it is advisable or necessary to prepare the dibromide in situ, that is, the dibromocarbene is liberated from tetrabro-momethane with methyllithium at -60 °C in the presence of the respective cyclopen-tene. Without workup, from the thus formed 6,6-dibromobicyclo[3.1.0]hexane, the 1,2-cyclohexadiene is then generated by addition of methyllithium at -30°C. 

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The tributyltin hydride mediated reaction of a (bromobutyl)cyclohexadienone affords the 6,6-m-annulated bicycle as the sole product32. The exclusive formation of the 6-cxo-product is caused by the rate-accelerating effect of the electron-withdrawing carbonyl group. A similar precursor with an unsubstituted cyclohexadiene gives a tricyclic product derived from 6-endo cyclization as a minor product. 

To overcome these problems with the first generation Brmsted acid-assisted chiral Lewis acid 7, Yamamoto and coworkers developed in 1996 a second-generation catalyst 8 containing the 3,5-bis-(trifluoromethyl)phenylboronic acid moiety [10b,d] (Scheme 1.15, 1.16, Table 1.4, 1.5). The catalyst was prepared from a chiral triol containing a chiral binaphthol moiety and 3,5-bis-(trifluoromethyl)phenylboronic acid, with removal of water. This is a practical Diels-Alder catalyst, effective in catalyzing the reaction not only of a-substituted a,/ -unsaturated aldehydes, but also of a-unsubstituted a,/ -unsaturated aldehydes. In each reaction, the adducts were formed in high yields and with excellent enantioselectivity. It also promotes the reaction with less reactive dienophiles such as crotonaldehyde. Less reactive dienes such as isoprene and cyclohexadiene can, moreover, also be successfully employed in reactions with bromoacrolein, methacrolein, and acrolein dienophiles. The chiral ligand was readily recovered (>90%). 

Yamamoto et al. have reported a chiral helical titanium catalyst, 10, prepared from a binaphthol-derived chiral tetraol and titanium tetraisopropoxide with azeotropic removal of 2-propanol [16] (Scheme 1.22, 1.23, Table 1.9). This is one of the few catalysts which promote the Diels-Alder reaction of a-unsubstituted aldehydes such as acrolein with high enantioselectivity. Acrolein reacts not only with cyclo-pentadiene but also 1,3-cyclohexadiene and l-methoxy-l,3-cyclohexadiene to afford cycloadducts in 96, 81, and 98% ee, respectively. Another noteworthy feature of the titanium catalyst 10 is that the enantioselectivity is not greatly influenced by reaction temperature (96% ee at... 

These reactions are found to be promoted by electron-donating substituents in the diene, and by electron-withdrawing substituents in the alkene, the dienophile. Reactions are normally poor with simple, unsubstituted alkenes thus butadiene (63) reacts with ethene only at 200° under pressure, and even then to the extent of but 18 %, compared with 100% yield with maleic anhydride (79) in benzene at 15°. Other common dienophiles include cyclohexadiene-l,4-dione (p-benzoquinone, 83), propenal (acrolein, 84), tetracyanoethene (85), benzyne (86, cf. p. 175), and also suitably substituted alkynes, e.g. diethyl butyne-l,4-dioate ( acetylenedicarboxylic ester , 87) ... 

The lack of selectivity in the reaction of unsubstituted tetrazole with 1,3-cyclohexadiene may be due to incomplete protonation of the substrate <2000H(53)1421>, as well as to the isomerization of the initially formed 2-substituted tetrazole 265 to the 1-substituted compound 264. Analogous isomerizations were reported for 2-/r 7-butyltetrazole <1998RJ0746> and 2-(l-adamantyl)tetrazole <1997RJ0571>. It was shown that pure tetrazole 265 in 87% phosphoric acid was slowly converted into isomer 264. After 4 days at room temperature, the isomer ratio 265 264 was 1 2.3 <2004RJ0598>. 

It should be noted that when the reaction of 1,3-cyclohexadiene was carried out not with unsubstituted tetrazole but with 5R-tetrazoles 24 (R = Me, Ph, CN4HCH2CH2), only the corresponding 2,5-disubstituted tetrazoles were isolated from the reaction mixture <2004RJ0598>. 

There is no exception to the regioselectivity rule that nucleophile addition proceeds by kinetic control at the unsubstituted internal position of the diene ligand. With 1-methoxy-l,3-cyclohexadiene, the addition/CO insertion/Mel quenching leads to a latent 1,4-dicarbonyl derivative (equation 80). With 2-methoxy-1,3-butadiene, the same conditions (but with protons instead of Mel) lead to a 3-methoxycyclopentanone that is very sensitive to acid, and can be readily converted to the corresponding cyclopentenone (equation 81). 

However, the cyclodimerization of 1,3-cyclohexadiene and also the addition of the cis,cis isomer of 2,4-hexadiene to 1,3-cyclohexadiene are only modestly stereoselective. The addition of cis,rra i-2,4-hexadiene to 1,3-cyclohexadiene is highly stereoselective for the addition to the lra s-propenyl group, but only modestly stereoselective for the addition to the cw-propenyl group. Further, the addition of a dienophile having a pendant, unsubstituted vinyl double bond to this diene is also highly endo stereoselective. The installation of a cis group at the terminus of the dienophilic moiety consistently appears to reduce the endo stereoselectivity to a more modest level. It has been proposed that the cis substituent attenuates the secondary interaction involving the endo double bond in the transition state for cycloaddition [47, 48]. The effect has been termed the cfs-propenyl effect . The addition of the ira j-anethole cation radical to both 1,3-cyclohexadiene and 1,3-cyclopentadiene is, however, only moderately diastereospecific (ca 3 1) [49]. 

Unsubstituted cyclic dienes, such as 1,4-cyclohexadiene, which contain both double bonds in the same ring, possess very low extinction coefficients at standard wavelengths. The reaction can be carried out by mercury sensitization" or under direct irradiation at 185 nm (equation 5). The next higher homolog, i.e. 1,4-cycloheptadiene, can be generated in the photolysis of bicyclo[4.1.0]hept-3-ene (5) and further transformed into the expected di-ir-methane product (6) at 185 nm (equation 6). ... 

Davies and coworkers exploited the utility of the cyclohexadiene system in short total syntheses of (+)-indatraline (95, Scheme 19) [90] and (+)-cetiedil (98, Scheme 20) [91]. In each case, an aryldiazoacetate (92 or 96) was used as the carbenoid precursor, Rh2(DOSP)4 as the catalyst, and unsubstituted 1,4-cyclohexadiene 93 as the substrate. The ultimate fate of the diene differed in each case in the indatraline synthesis it was ultimately oxidized to a benzene ring with DDQ, and in the preparation of cetiedil it was reduced to a cyclohexane with H2 and Pd/C. 

Unsaturated AT-chlorosulfonyl-jft-lactams are generally unstable and readily rearrange to the product of formal 1,4-addition. Thus, the reaction of 1,3-cyclohexadiene with CSI at room temperature affords a quantitative yield of adduct 150. Hydrolysis of 150 with benzenethiol in the presence of pyridine gives 151 in 67% yield. When the reaction mixture of CSI and 1,3-cyclohexadiene was refluxed in chloroform, 152 was formed in 90% yield as a viscous oil. Hydrolysis of 152 with aqueous NaOH gave iV-unsubstituted lactams in 35% yield. 2-Azabicyclo[2.2.2]octene (153) can be conveniently prepared by reduction of 152 with LiAlH4 after hydrolysis (equation 81)76. 

It is apparent from Table 6 that methyl and methoxy substituents enhance the reactivity of butadiene and anthracene, while chlorine atoms decrease that of butadiene and cyclopentadiene, towards electrophilic dienophiles. Phenyl substituents have very different effects in positions I and 2 [columns (i) and (iv)] here the substituent is large enough to exert a marked steric influence on the cisoid transo/c/equilibrium of the diene, so that the conformation of 2-phenyl-butadiene is favoured, and therefore the overall reactivity of 2-phenyl-butadiene is enhanced, while trans-1 -phenyl-butadiene is little affected. Cyclic unsubstituted dienes are more reactive than butadiene however, the difference between cyclopentadiene and cyclohexadiene is enormous the high reactivity of the former must be in part attributed to factors other than the cisoid conformation. 

Organometallic addition takes place at an a-position, or occasionally at C-4 when the a-positions are substituted and C-4 is unsubstituted, or with organocuprates. The initial 2//-pyrans undergo electrocyclic ring opening (and more rapidly than the comparable cyclohexadiene/hexatriene transformation ) affording dienones or dienals. 

Nucleophilic attack on neutral complexes of ii -diene ligands is less common than attack on cationic complexes of these ligands but is known. In one case, Semmelhack reported the reactions of iron complexes of acyclic ii -dienes with reactive carbanions such as LiC-MCjCN and LiCHPhj (Equation 11.47). At -78 °C, the reaction is rapid, and kinetically controlled. Attack occurs at an unsubstituted, internal position to give an unstable o-alkyl Ti -olefin complex. This addition is reversible below 0 °C, and the more stable product is then generated from nucleophilic addition at a terminal position of the diene to give the thermodynamically more stable T -allyl complex. Cyclohexadiene complexes are similarly alkylated by a range of carbanions. ... 

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