Cycloadditions of bis-dienes

Bis-o-quinodimethanes have also been used to functionalize [60]-fullerene by Diels Alder reaction. An example is the preparation of main-chain polymers with incorporated [60]-fullerene units [48] illustrated in Scheme 2.20. Cycloaddition of bis-diene 50 generated in situ from bis-sulfone 49 with [60]-fullerene leads to an oligomer mixture 51. Another type of functionalization is based on the... 

Diels-Alder Reaction in Unconventional Reaction Media Intramolecular Diels-Alder cycloadditions of bis-diene substrates [94]... 

The first metal-catalyzed [4 +2]-reaction of tethered dienes with 7r-systems was reported by Wender and Jenkins using alkynes initially as the two-carbon component.21 This study was based on the earlier observation by Wender and Ihle that in the [4 + 4]-cycloaddition of bis-dienes a competing side-reaction is the [4 + 2]-cycloaddition of the diene with a mono-ene portion of a second diene. The extension of this reaction to the synthesis of seven-membered rings by trapping the metallacycloheptadiene with CO, a formal [4 + 2 + l]-cycloaddition, has been shown in preliminary studies to be feasible. For example, tethered diene-yne 160 can be converted to cycloheptadienone 163 in an Rh(l)-catalyzed [4 + 2 + l]-reaction with CO, albeit the [4 + 2]- and [2 + 2 + l]-reaction products dominate (Equation (29)). The mechanistic scheme (Scheme 44) illustrates the possible metallacyclic intermediates leading to the observed products and provided the conceptual basis for the realization of three novel reaction types ([4 + 2], [2 + 2 + 1], and [4 + 2 + 1 ]).1... 

This method provides the basis for a general and efficient route to alkyl-substituted and heterofunctionalized bicyclo[6.4.0]dodecanes and to bicyclo[5.3.1]undecanes. In several model studies, the nickel-catalyzed intramolecular [4 + 4] cycloaddition of bis-dienes has been applied to the construction of diterpene systems, such as taxol (7), crispolide, and vulgarolide13 1S. Thus, in the case of taxol. both AB- and BC-ring fusion is achieved with high yield and high diastereoselectivity13. 

With these results in mind, we were attracted to two key points. The first was that building the complex bicyclic core system (20), with the four stereocenters as desired, could be achieved by diene-ene [2+2+1] cycloaddition of bis-diene (21) followed by reduction. The second attractive point was the diversification that could be achieved by cross metathesis at a late stage to get different analogs from the same bicyclic core (20). As a result, a retro-synthesis was conceived (Scheme 1) of isocarbacyclin methyl ester, or clinprost (3), having only nine steps.The first part of the synthesis, and most difficult part, was to generate bis-diene (21). 

Our initial studies focused on the transition metal-catalyzed [4+4] cycloaddition reactions of bis-dienes. These reactions are thermally forbidden, but occur photochemically in some specific, constrained systems. While the transition metal-catalyzed intermole-cular [4+4] cycloaddition of simple dienes is industrially important [7], this process generally does not work well with more complex substituted dienes and had not been explored intramolecularly. In the first studies on the intramolecular metal-catalyzed [4+4] cycloaddition, the reaction was found to proceed with high regio-, stereo-, and facial selectivity. The synthesis of (+)-asteriscanoHde (12) (Scheme 13.4a) [8] is illustrative of the utihty and step economy of this reaction. Recognition of the broader utiHty of adding dienes across rc-systems (not just across other dienes) led to further studies on the use of transition metal catalysts to facilitate otherwise difficult Diels-Alder reactions [9]. For example, the attempted thermal cycloaddition of diene-yne 15 leads only... 

It was clear that 1 would be derived from a Diels-Alder adduct. There has been a great deal of work in recent years around the development of enantioselective catalysts for the Diels-Alder reaction, but the catalysts that have been developed to date only work with activated dienophile-diene combinations. For less reactive dienes, it is still necessary to use chiral auxiliary control. One of the more effective of those was the known camphor-derived tertiary alcohol, so that was used in this project. Diels-Alder cycloaddition of the diene 4 with the enantiomerically-pure enone 5 led to the adduct 6 with high diastereocontrol. Oxidative cleavage led to the acid 7, which was carried on to the bis-enone I. 

Bi- and tricyclic carbocyclic ring systems can be easily obtained from (1-alkynyl)carbene complexes in two or more reaction steps without isolation of intermediate products. For example, the bicyclic 1,3-dienone 44 has been generated from compound le in a two-step cycloaddition/annulation procedure involving [4+2] cycloaddition of a diene to the C=C bond of a (l-alkynyl)carbene complex and a subsequent Dotz reaction.68 Furthermore, a 1,4-dioxy dihydronaphthalene 45 was obtained from the silyl derivative lg in a similar reaction sequence. In contrast to the methyl derivative 44, the corresponding silyl derivative generated from lg undergoes facile... 

The enantioselective cycloaddition of thiabuta-dienes with the acrylate 55 yielding dihydrothio-pyranes was conducted with optical yields up to 98 % ee using a C2-symmetric bis(oxazoline) ligand derived from l-amino-indan-2-ol [29]. 

Reaction of bis-diene 179 with benzyne gives both the mono-adduct 180 and the bis-adduct 181. Cycloaddition of 3-methoxybenzyne to diene 182 was regioselective, giving, after dehydrogenation, 183 and 184 in a 4 1 ratio. 

Perfluoroalkyl groups adjacent to multiple bond systems lower the frontier molecular orbitals (FMOs) Therefore, cycloaddition reactions preferentially occur with electron-rich multiple-bond systems The preference of bis(trifluoromethyl)-substituted hetero-l,3-dienes for polar reacuons makes them excellent model compounds for developing new types of diene reactions deviating from the well documented Diels-Alder scheme (pathway 1) A systematic study of the reactions of diene (1 =2-3=4)-dienophile (5=6) combinations reveals new synthetic possibilities that have not yet been fully exploited as tools for preparative organic cherrustry (equation 25)... 

Cycloaddition reactions where bis(trifluoromethyl)-substituted hetero-1,3-dienes act as dienophiles have been descnbed for open-chain and cyclic dienes [115, 126, 127] The balance of the diene -dienophile activity of bis(tnfluoro-methyl)-substituted hetero-l,3-dienes can be influenced strongly by the substituents bonded to the inuno nitrogen atom For instance, A/-(arylsulfonyl) denvatives of tnfluoroacetaldimine and hexafluoroacetone imine do not act as dienes but exhibit only the dienophile reactivity of electron deficient imines [5 229, 234,235, 236 237] (equation 52)... 

The reactions of bis(trifluoromethyl)-subsatuted hetero 1,3 dienes are predomi nantly LLJMO controlled processes [238] With polar or highly polarizable dieno philes, the tendency to undergo stepwise cycloaddition reactions is considerable Notably these hetero-1,3-dienes react with a,(l unsaturated hetero multiple bond systems across the hetero multiple bond exclusively [243, 246 248] (equation 53)... 

An alternative synthesis of 9//-tribenz.[/ >,ia, /]azepine (65, R = H) involves cycloaddition of 10,1 l-dehydro-5i/-dibenz[/t,/]azepine (66), generated from 5-acetyl-10-bromo-5//-dibcnz[/ ,/]azepine, with cyclohexa-1,3-diene.8 The cycloadduct 67, so-formed, with potassium rm-butoxide in refluxing bis(2-methoxyethyl) ether (diglyme) undergoes hydrolysis and loss of ethene to give the tribenzazepine in 39% yield. 

Another versatile two-step synthesis of homobarrelenones [45] is based on the high pressure cycloaddition of tropone (125) and its 2-methoxy-, 2-hydroxy- and 2-chloro-derivatives with 2,3-bis(methoxycarbonyl)-7-oxabicyclo[2.2. l]hepta 2,5-diene (133) followed by thermolysis of the cycloadducts at 130 °C with the... 

Hoomaert has studied Diels-Alder reactions of pyridine oquinodimethane analogs generated from functionalized o-bis(chloromethyl)pyridines <96T(52)11889>. The photochemical cycloaddition of 2-alkoxy-3-cyano-4,6-dimethylpyridine with methacrylonitrile gives a bicyclic azetine, 6-alkoxy-3,5-dicyano-2,5,8-trimethyl-7-azabicyclo[4.2.0]octa-2,7-diene, in moderate yield <96CC1349>. Regiospecific hydroxylation of 3-(methylaminomethyl)pyridine to 5-(methylaminomethyl)-2-(17/)-pyridone by Arthrobacter ureafaciens has been reported <96MI173>. 

The [4+ 4]-cycloaddition reaction of tethered bis-dienes has been used by Wender and co-workers in total synthesis as exemplified in syntheses of ( )-salsolene oxide and (-l-)-asteriscanolide (Scheme 28). In the synthesis of ( )-salsolene oxide, a nickel(0)-catalyst cleanly effects the cycloaddition of the two conjugated dienes in compound 93 to afford the bicyclo[5.3.1]undecadiene in a good yield and with moderate selectivity.99 The first synthesis of (-l-)-asteriscanolide was accomplished in only 13 steps. The key [4+ 4]-cycloaddition reaction efficiently set the requisite eight-membered ring of (-l-)-asteriscanolide in good yield and with excellent diastereoselectivity.100 The diastereoselective [4 + 4]-cycloaddition has also been applied to the synthesis of the core ring system found in several sesterterpenes such as the ophiobolins (Scheme 28).101... 

A more practical BLA has been designed to improve the scope of dienophiles in reactions with less reactive dienes. 3,5-Bis(trifluromethyl)-phenylboronic acid (80) was chosen as the Lewis acidic metal component in the new BLAs 77-79. These new BLAs show higher catalytic activity in enantioselective cycloaddition of both a-substituted and a-unsubstituted a,/ -enal with various dienes. 

Corey and co workers2056, 24X reported the reactive cationic oxazaborinane catalyst and afforded 398a which promoted cycloadditions between cyclopentadiene and several a,/J-cnals good enantioselectivities. Excellent results were obtained in cycloadditions of several modestly reactive dienes to a-bromoacrolein in the presence of catalyst 398b having tetra[3,5-bis(trifluoromethyl)phenyl]borate as the counterion (Table 23). 

The reaction of 1,4-diphenylbuta-l,3-diene (2) with trithiazyl trichloride (3) yields a bi(thiadiazole) (4), an isothiazoloisothiazole (5), a dithiazolothiazine (6), and two thiazin-odithiatriazepines (7) and (8) by 1,2-, 1,3-, and 1,4-cycloaddition reactions (Scheme 2). The bridged-mode (/3-tether) tandem inter-[4 -E 2]/intra-[3 -E 2] cycloaddition of (ii)-2-methyl-2-nitrostyrene (9) with 1-butoxypenta-1,4-diene (10) produces stable tricyclic nitroso acetals (11) which afford, after reduction and protection, highly functionalized aminocyclopentanedimethanol triacetates (12) (Scheme 3). ... 

Beside [2+2+2] cycloaddition, [4+2] and [5+1] cycloadditions represent other approaches for the construction of six-membered ring systems. In parhcular, the intermolecular and intramolecular [4+2] cycloadditions of diene and alkyne have been extensively studied, and a variety of transition-metal complexes-including those of Fe, Ni and Rh-have been reported as efficient catalysts. The first enanh-oselective reaction was achieved with a chiral Rh complex, although the substrates were limited to dienynes with a substituent on the diene terminus [36]. Later, Shibata and coworkers developed an intramolecular and enanhoselective [4+2] cycloaddition using an Ir-BDPP (l,3-bis(diphenylphosphino)pentane) complex (Scheme 11.24) [37], where dienynes with an unsubstituted diene terminus were transformed into bicyclic cyclohexa-1,4-diene with up to 98% ee. 

Along with homopolymerization, copolymerization has also been studied within the framework of initiation by tris(4-bromophenyl)ammoniumyl hexachloroantimonate (Bauld et al. 1998a). Generally, cation-radical cycloaddition occurs more efficiently when the reactive cation-radical is the ionized dienophile (Bauld 1989, 1992). In the cited work on copolymerization, the bis(diene) was chosen to be resistant against ionization by the initiator used. As to the dienophile functionality, propenyl rather than vinyl moieties were selected because terminal methyl groups sharply enhance the ionizability of the alkene functions. The polymerization shown in Scheme 7.18 was performed in dichloromethane at 0°C. 

The bis-dienes 13-15 form ladder-type bis-fullerene adducts. Cycloadditions proceed in good yields also with electron-deficient dienes such as 21-23. Porphyrin donor systems such as 25 or 30 or quinoidal acceptor systems such as 19 and 20 were introduced to study the properties of the charge transfer in Cjq donor-acceptor systems. 

Singlet oxygen reacts through the [4- -2]-cycloaddition mode with the sterically hindered and non-planar 1,3-diene system in l,l -dimenthene (493) to afford the cis-endoperoxide 494, albeit in moderate yield (Scheme 135) ". Cycloaddition of O2 to more planar bis(dialine) (495) proceeds smoothly leading predominantly to the trans-endoperoxide trans-496 (70%), while cis-496, which would be expected to derive from a concerted process, constitutes the minor (15%) product (Scheme 136) . 

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