Hetero Diels-Alder reaction high pressure

In Scheme 14 the effect of pressure on Diels-Alder reactions with acyclic heterodienophiles or heterodienes is presented. The application of high pressure leads also in these reactions to an enhancement of rates and improvement of yields. The hetero-Diels-Alder reaction (entry 3) is a good example of the interplay between pressure and temperature. At high pressure the rate of reaction as well as the diastereoselectivity are increased. The pressure-induced acceleration allows the temperature of reaction to be lowered, which leads to a further increase of diastereoselectivity. 

Hanessian and Compain have also reported a Lewis acid-promoted inverse electron demand hetero-Diels-Alder reaction between dihydrofurans and dihydropyrans with a-keto-/3,7-unsaturated phosphonates to give stmcturally related products <2002T6521>. High-pressure OTr/o-selective hetero-Diels-Alder reactions between a,/3-unsaturated aldehydes and enol ethers in the presence of lanthanide catalysts have also been reported and give 3,4-dihydro-27/-pyrans. Examples include the use of cyclic enol ethers to give 2,3,4,4a,5,8a-hexahydro-277,577-pyrano[2,3-. ]pyrans <1995T8383>. 

The hetero-Diels-Alder reaction of activated butadienes with carbonyl compounds is a convenient method for the preparation of precursors of sugars. Up to three chiral centers are created simultaneously. The high-pressure [4 + 2]cycloaddition of l-methoxybuta-1,3-diene 32 to N-mono- and N,N-diprotected alaninals was investigated [42-45]. The Eu(fod)3-mediated reaction of 32 with alaninal 25 gave a mixture of four diastereoisomers, which was then subjected to acidic isomerization, leading to the thermodynamically more stable pair of adducts syn-33 and anti-34, with predominance of the latter isomer (Scheme 12). The N-monoprotected alaninals reacted with a moderate ryn-diastereoselectivity. This method was used in the synthesis of purpurosamines (see Sec. DI.C). 

The reaction rate and the selectivity of hetero Diels-Alder reactions can also be influenced by applying high pressure. A large amount of knowledge has been... 

Good results were also obtained with lithium perchlorate in dichloromethane and diethyl ether. It has been shown that the lithium cation acts as a Lewis acid and the effects are not due to an internal pressure [80]. The acceleration is much more pronounced for hetero Diels-Alder reactions as compared to the allcarbon cycloadditions. With chiral aldehydes a high level of chelation control has been observed (see later) [81,82]. 

Furthermore, azo dienophiles have been employed in diene-transmissive hetero Diels-Alder reactions of cross-conjugated trienes which allow the straightforward construction of polycyclic compounds [297]. Theoretical interest has been directed to the hetero Diels-Alder reaction of diethyl azo di-carboxylate with 1,3-cyclohexadiene whose concerted course was demonstrated by means of a high pressure study [298]. 

In early work which have been summarized very recently [23], Danishefsky et al. have investigated hetero Diels-Alder reactions of carbonyl compounds in order to yield glycals. Numerous further contributions to the stereoselective synthesis of dihydropyran derivatives by high pressure or Lewis acid induced Diels-Alder reactions of carbonyl compounds have been made by Jurczak et al.,... 

High Pressure Applications in Hetero Diels-Alder Reactions... 

Comparable results were also obtained in the hetero Diels-Alder reaction of 8-1 and 8-5. Again, the ratio of the products 8-6 and 8-7 was not changed under high pressure (Fig. 8-2) [541]. 

Vandenput et al. applied high pressure to perform hetero Diels-Alder reactions with unactivated 1-oxa-1,3-butadienes such as 8-8 and enol ethers 8-9 in the presence of a weak Lewis acid. The cycloadditions led to the dihydropyrans 8-10 as a mixture of diastereomers in 23 to 85% yield (Fig. 8-3) [543]. 

An effect of high pressure on the diastereoselectivity is also observed for intramolecular hetero Diels-Alder reactions as found for the cycloaddition of the benzylidene-isoxazolone 8-23 to afford the cis-annulated 8-24 as the major product together with the frans-diastereomer 8-25 (Fig. 8-8) [549], However, the difference in activation volume with AAV =1.6 0.2 cm3 mol"1 is rather small. The activation volume with AV = 19.6 0.5 cm3 mol-1 at 343 K lies significantly below the usual values found for intermolecular cycloadditions of 1-oxa-1,3-butadienes, indicating that this reaction may be on the border line to a two-step reaction but see also below. 

Some older examples of the application of high pressure in hetero Diels-Alder reactions are found in excellent reviews and books on this topic [552-561]. In addition a few hetero Diels-Alder reaction under high pressure have already been mentioned in the foregoing chapters. 

As already mentioned, hetero Diels-Alder reactions can be accelerated by applying Lewis acids and high pressure. However, also the application of microwaves can increase the reaction rate [574], Thus, the usually little reactive methyl vinyl ketone 9-19 cycloadded to highly sensitive ketene acetals such as 9-18 within 10 min at 20 °C under microwave irradiation to give the dihydropyran 9-20 in 69% yield. Using other ketene acetals yields of up to 95% could be achieved (Fig. 9-6). 

The multitude of hetero Diels-Alder reactions found in the literature clearly demonstrates the importance of this transformation. Thus, this type of cycloaddition is today one of the most important methods for the synthesis of heterocycles. Striking features of this method are the tremendous diversity, excellent efficiency especially in those cases where the reactive dienes and dienophiles are formed in situ, and high stereoselectivity in many cases. There is a broad scope and only little limitation. In recent years the use of Lewis acid, the development of diastereoselective and enantioselective reactions as well as the application of high pressure gave an enormous push. In addition, many of the obtained heterocycles can be transformed into acyclic compounds allowing the stereoselective preparation of e.g. amino and hydroxyl functionalized open chain compounds or even carbocycles to be of interest. Also, for the synthesis of natural products, the hetero Diels-Alder reaction is of great value. Since heterocycles,... 

Tietze and Schuffenhauer explored the intermolecular hetero Diels-Alder reaction of ethyl vinyl ether and sulfinimine 204 and found that at high pressures (11 kbar) and long reaction times (48 h at room temperature), tetrahydropyridines 205 and 206 were obtained in 96% yield and in a ratio of 1.7 1.107 The exo-adducts were not observed. Phenyl vinyl sulfide reacts similarly, but simple alkenes failed. Theoretical calculations and the experimental results suggest that while the cycloaddition is concerted, it is highly asynchronous. 

Enamino ketones, e.g. 1. react with various enol ethers in hetero-Diels Alder reactions, with inverse electron demand - yields are high. Reactions are regioselective, but not stereoselective. Although the endo approach is favored, stereoselectivity also depends on the EjZ configuration of the heterodiene. The use of high pressure (3.75 MTorr) improves the endo selectivity. ... 

The enantioselective total synthesis of the Securienega alkaloid (-)-phyllanthine by S.M. Weinreb et al. involved a stereoselective Yb(OTf)3-promoted hetero Diels-Alder reaction between a cyclic imine dienophile and Danishefsky s diene This was the first example of using an unactivated cyclic imine in this type of cycloaddition. Commonly used Lewis acid catalysts (e.g., SnCb, TiCU, etc.) produced only low yields of the desired cycloadduct. However, it was discovered that ytterbium triflate catalyzed the cycloaddition and afforded the product in 84% yield. Later they also found that the cyclization could occur at high pressure and in the absence of the catalyst, although a slightly lower yield (71%) of the product was obtained. 

Jurczak has reported an interesting approach to optically active 6-substituted-2-methoxy-5,6-dihydropyrans. The approach is based on a high-pressure catalysed hetero-Diels-Alder reaction of activated diene 49 with non-activated heterodienophile 52 (Scheme 7.13). These authors studied the eifects of catalyst... 

Generally, the electrocyclic cycloaddition reactions are performed thermally, without catalysis. Diels-Alder reactions are further facilitated by high pressure in hydrophobic structures, suffering hydrophobic collapse within an aqueous environment. Photochemical cycloadditions are often limited by the penetration of the polymeric support by the light of the desired wavelength. However, especially in case of hetero Diels-Alder reactions, Lewis acid catalysis has been applied. On a solid support the use of acid catalysis is often limited by the stability of the support linker, since most common linkers have been designed to be cleavable under acidic conditions. Table 4 shows some of the Lewis acids and the support link used. 

Al-Badri, H., Maddaluno, J., Masson, S., and Collignon, N., Hetero-Diels-Alder reactions of a-carbonylated styrylphosphonates with enol ethers. High-pressure influence on reactivity and diastereoselectivity, J. Chem. Soc., Perkin Trans. I, 2255, 1999. 

An important development in the hetero Diels-Alder reaction came when Jurczak used high pressure to help improve the reactivity of dienes with aldehydes. 1-Methoxybutadiene, for example, was shown to react at 15-25 kbar (I bar = l(X) kPa) with a variety of unactivated aldehydes. - These reactions give predominantly endo adducts and allow for the use of simple alkyl and aromatic aldehydes as dienophiles. Jurczak also realized the importance of this reaction in the synthesis of carbohydrates and applied it to the construction of simple monosaccharide derivatives (see Section 2.5.2. ). " ... 

The hetero-Diels-Alder reaction with inverse electron demand is an attractive route for the synthesis of 3.4-dihydro-2//-pyrans. Enone 7, esterified with D-mandelic acid as chiral auxiliary, adds to ethyl vinyl ether (8) to give a 2 1 mixture of 9 and 10 [d.r. (2S,4S) (2RAR) 67 33]1. The enone 11 requires high pressure to add to the much less reactive enol ether 12, yielding a 2 3 mixture of 13 and 14 [d.r. (2S, 3S,45 )/(21 ,37 ,4/ ) 40 60]8. The introduction of the additional stereogenic center in the enone 15 leads to a substantially improved diastereofacial selectivity, and adducts 16 and 17 are obtained as a 1 10 mixture [d.r. (2S.4S) (2RAR) 9 91]9. 

The hetero-Diels Alder reaction of nonactivated carbonyl compounds requires activation before a successful cycloaddition reaction occurs. In general, three methods are available Lewis acid catalysis, elevated temperature and elevated pressure. In some cases, when elevation of temperature causes the destruction of reactants before the cycloaddition takes place or if one or both reactants are very susceptible to Lewis acid catalysis, the method of choice is high pressurel9. For the reasons mentioned above, the Diels Alder reaction of 2,3-O-isopropylidene-D-glycer-aldehyde (2) with 1-methoxy-l,3-butadiene (1) was performed under high pressure. Extensive studies on the influence of parameters, such as pressure, temperature and solvent, on the yields and diastereoselectivities of the [4 + 2] cycloaddition enabled the optimal conditions to be determined20. 

A common problem in Diels-Alder reactions is the regioselectivity. It is usually controlled by the coefficients of the interacting orbitals in the transition structures and can be improved in many cases by using Lewis acids. However, the application of high pressure also has a great influence as shown for the intramolecular hetero-Diels-Alder reaction of the benzylidenebarbituric acid derivative 48 (Scheme 8.13). In this transformation the ortho-adduct 49 and the meta-adduct 50 are formed. 

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