Activation of the Diene

The hydroamination of 1,3-dienes has been attempted with catalyst precursors of nearly all transition metals. The most active are those based on Group 9 and 10 transition metals. 

3-Butadiene and isoprene give rise to mixtures of what are usually called telom-ers, namely 1 1 telomers between the amine and the 1,3-diene (trae hydroamination products), 1 2 telomers and even higher homologs together with oligomers of the diene as exemplified in Eq. (4.41). 

The ratio of formahon of 1 1 vs. 1 2 telomers does not appear to be solely a function of the metal but is also determined by the nature of the added ligands and of the co-catalysts (additives). Higher dienes like 1,3-pentadiene, 2,3-dimethylbutadiene, etc. afford 1 1 telomers only. 

In fact, catalytic systems which effect solely the hydroamination of 1,3-butadiene and isoprene are rare and usually specific to the diene and to the amine. Thus morpholine adds to 1,3-butadiene in the presence of RhCf.lHjO to give a mixture of 1,2-(Markoviiikov) and 1,4-hydroamination products in good overall yield (Eq. 4.42) [171,172). 

Although less active, the cobalt system CoCl2/PPh3/NaBH4 affords a 90/10 mixture of 1,2- and 1,4-addition products in 98% yield at room temperature [172]. Palladium catalysts are more efficient (Eq. 4.43) [173]. 

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Activation of the diene system must be present in order for any cycloaddition to occur under experimentally feasible conditions 42. In fact, distillation of ethyl ( )- and/or (Z)-6-azido-2-vinyl-2-hexenoate produced the same mixture of cis- and trans- isomers of vinylaziridines 4, although only one isomer was isolated, the other one was converted during purification to a monocyclic dihydropyrrole143. Although the stereochemistry was lost after conversion to the bicyclic dihydropyrrole, further reduction and isomerization steps were utilized in order to obtain the desired alkaloids diastereoselectively143,144... 

The majority of cases (Table 1) involve activation of the diene by complexation to Pd(II) and Pt(II) centers. However, other metal-diene complexes have been examined including Ni(II), Ir(I), and Mn(I) complexes. Cationic or neutral complexes are used in the nucleophilic addition reactions. The most common nucleophiles employed are oxygen or nitrogen bases (hydroxide, alkoxides, carboxylates, amines) or stabilized carbon nucleophiles (malonate, j8-diketonates). The dienes employed include 1,5-cyc-looctadiene, norbomadiene, dicyclopentadiene, 4-vinylcyclohexene, 7-(alkylidene)nor-bornene and endo-4-vinylnorbornene. 

The diene (109) is formed when the keto-diene (110) is irradiated in various solvents using A = 254 nm." The Diels-Alder activity of the diene (109) was... 

The reaction barrier firmly supported our previous finding that 1,3,4-oxadiazole should react with highly reactive dienophiles. In fact, it was predicted that the reaction between 1,3,4-oxadiazole and cyclopropene should be possible under moderate reaction conditions (room temperature). For reactions with dienophiles of low reactivity such as ethylene, forceful reaction conditions or even activation of the diene or dienophile are required. Both 1,3,4-triazole and 1,3,4-thiadiazole were predicted to have activation barriers that were 6 kcal/mol and correspond to comparable reactivities. In all cycloaddition reactions with cyclopropene as a dienophile, an exo cycloadduct is predicted to be a major or exclusive product, which is in agreement with some of our previous studies of cycloaddition reactions with furan as a diene and cyclopropene as a dienophile. 

Activation of the diene can be achieved by the introduction of an electron-donating nitrogen substituent. In nitroalkenes the nltro-group serves as an activating and regiocontrolling functionality, that can be readily removed or further functionalized after the cycloaddition reaction. 

Conjugated dienes coordinated to a transition metal can readily be transformed into a rr-allylmetal complex by functionalization at the 4-position.f This makes dienes useful substrates for catalytic transformations since the 7r-allyl complex formed can undergo further reaction. t A number of Pd-catalyzed reactions of conjugated dienes are known that proceed via rr-allylpalladium intermediates and lead to useful 1,4- or 1,2-funtional-ization of the diene. There are two types of reactions of this kind (i) Pd(0)-catalyzed reactions that involve initial oxidative addition and (ii) Pd(II)-catalyzed reactions that involve electrophilic activation of the diene by the metal followed by nucleophilic attack. This section deals with C— N and C—O bond formation via these two types of reactions. This topic has previously been reviewed in connection with Pd-catalyzed additions to conjugated dienes. [5] [n] -jijg present review will focus mainly on the work published since 1997 but will also briefly discuss previous work. 

The Diels-Alder Reaction consists in the direct combination of a compound containing a conjugated diene system u ith a reagent which possesses a double or triple bond activated bj suitable adjacent groups. Examples of such reagents are maleic anhydride, p-benzoquinone, acraldehyde and acetylene dicarboxylic esters. Combination always occurs at the 1,4 positions of the diene system ... 

Compounds containing a double or triple bond, usually activated by additional unsaturation (carbonyl, cyano, nitro, phenyl, etc.) In the ap position, add to the I 4-positions of a conjugated (buta-1 3-diene) system with the formation of a ax-membered ring. The ethylenic or acetylenic compound is known as the dieTwphile and the second reactant as the diene the product is the adduct. The addition is generally termed the Diels-Alder reaction or the diene synthesis. The product in the case of an ethylenic dienophile is a cyctohexene and in that of an acetylenic dienophile is a cyctohexa-1 4-diene. The active unsaturated portion of the dienophile, or that of the diene, or those in both, may be involved in rings the adduct is then polycyclic. 

Figure 1.2. Endo and exo pathway for the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone. As was first noticed by Berson, the polarity of the endo activated complex exceeds that of the exo counterpart due to alignment of the dipole moments of the diene and the dienophile K The symmetry-allowed secondary orbital interaction that is only possible in the endo activated complex is usually invoked as an explanation for the preference for endo adduct exhibited by most Diels-Alder reactions.

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)... 

Covalent fluondes of group 3 and group 5 elements (boron, tin, phosphorus, antimony, etc ) are widely used m organic synthesis as strong Lewis acids Boron trifluoride etherate is one of the most common reagents used to catalyze many organic reactions. A representative example is its recent application as a catalyst in the cycloadditions of 2-aza-l,3-dienes with different dienophiles [14] Boron trifluoride etherate and other fluonnated Lewis acids are effective activators of the... 

Photo-induced Diels Alder reaction occurs either by direct photo activation of a diene or dienophile or by irradiation of a photosensitizer (Rose Bengal, Methylene Blue, hematoporphyrin, tetraphenylporphyrin) that interacts with diene or dienophile. These processes produce an electronically excited reagent (energy transfer) or a radical cation (electron transfer) or a radical (hydrogen abstraction) that is subsequently trapped by the other reagent. 

Thompson, S. and Smith, M.T. (1985). Measurement of the diene conjugated from of linoleic acid in plasma by high performance liquid chromatography. A questionable non-invasive assay of free radical activity. Chem. Biol. Interactions 55, 357-366. 

Cycloaddition reactions often require the use of harsh conditions such as high temperatures and long reaction times. These conditions are not compatible with sensitive reagents or products such as natural products. The applicability of Diels-Alder cycloadditions is, moreover, limited by the reversibility of the reaction when a long reaction time is required. The short reaction times associated with microwave activation avoid the decomposition of reagents and products and this prevents polymerization of the diene or dienophile. All these problems have been conveniently solved by the rapid heating induced by microwave irradiation, a situation not accessible in most classical methods. With the aid of microwave irradiation, cydoaddition reactions have been performed with great success [9, 10]. 

Although Pd-based catalyst systems form only the desirable trans-1,4-hexadiene, their industrial value is very doubtful because of the reported poor yield of the C6 diene and the very low activity of the dimerization reactions compared to other catalyst systems. 

The diene rule has had much importance in the interpretation of the optical activity of distorted dienes, as in the case of occidentalol, epi-occidentalol and fraws-occidentalol, 10, 11 and 12, respectively17. 

Furthermore, for both 28 and for 26, MM calculations indicate that even the individual double bonds are highly twisted (15-20°). This could be (vide infra) a further mechanism giving rise to optical activity of the tt-tt transition of the diene chromophore. 

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