Diels-Alder reaction regiospecificity

As orbital control is implicit in the soft-soft interactions of the HSAB principle, it should be possible to deflne qualitatively the various aspects of the Diels-Alder reaction. Regiospecificity between dissymmetrical addends is found to arise from preferential formation of the first bond between the softest centers of the partners (29). 

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 first photochemical reactions to be correlated with PMO theory were the dimerizations of anthracene, tetracene, pentacene, and acenaphthylene. 36> More detailed energy surfaces for the photodimerization reactions of butadiene have also been calculated. 30> In the category of simplified calculations lie studies of the regiospecificity of Diels-Alder reactions 37>, and reactivity in oxetane-forming reactions. 38,39) jn these... 

Electron-withdrawing groups attached to the dienophile accelerate the rate of the reaction, donating groups decrease it. For the diene, the opposite is true. Because of the high regiospecificity and the tolerance of a wide number of functional groups, the Diels-Alder reaction is of considerable synthetic importance. 

The explanation of the regiospecificity of Diels-Alder reactions requires knowledge of the effect of substituents on the coefficients of the HOMO and LUMO orbitals. In the case of normal electron demand, the important orbitals are the HOMO on the diene and the LUMO on the dienophile. It has been shown that the reaction occurs in a way which bonds together the terminal atoms with the coefficients of greatest magnitude and those with the coefficients of smaller magnitude [18]. The additions are almost exclusively cis and with only a few exceptions, the relative configurations of substituents in the components is kept in the products [19]. 

The challenging question can be raised as to whether the formation of 109 can be explained in an alternative way, i.e., by a Diels-Alder reaction with an inverse electron demand, in which the C = N group of the electron-rich benzamidine forms a regiospecific cycloadduct across the 1,4-position... 

Diels-Alder reactions.1 This sulfone can serve as an equivalent in Diels-Alder reactions to ethylene, which is not reactive. An added attraction of this reaction is that the adducts can be alkylated regiospecifically. 

Diels-Alder reactions. This ketene does not undergo [2 + 2]cycloadditions, but does undergo regiospecific Diels-Alder reactions with moderately reactive dienophiles. 

CR(C)(282)357). Another Diels-Alder reaction which has been recently demonstrated is that with 6-acetoxy-2,6-dihydropyran-3-one (671), which is a precursor of the pyrylium zwitterion (673). When heated with propenal, it gives the adduct (672) which consists of a mixture of 4 1 of the exo endo isomers, but all reactions are regiospecific (80JOC3361). 

Azide addition to enolizable ketones is regiospecific and may be considered as a 1,3-dipolar cycloaddition occurring at the double bond of the enolate, similar to the addition of azides to electron-rich olefins. However, a stepwise reaction appears more probable because glycosyl azides exhibit anomerism when they react with activated methylene compounds, thus indicating the presence of a triazene intermediate.264 On the other hand, the formation of the triazene intermediate may be considered as a limited case of 1,3-dipolar cycloaddition where one of the bonds is formed completely before the other one starts,2 such a limited case being observed for the Diels-Alder reaction.265... 

The facially perturbed enantiopure (.S, .S )-2-(p-tolylsulfinyl)norborncno-/7-bcnzoquin-ones (119), undergo asymmetric Diels-Alder additions with cyclopentadiene to yield the four possible adducts (120) and (121). The endo-syn cycloadducts (121) can be used in the synthesis of the cage compound garudane (122) (Scheme 44).234 The antiaromatic compound 1,4-biphenylenequinone (123) has been synthesized and trapped by Diels-Alder reaction with cyclopentadiene (Scheme 45).235 The 4 + 2-cycloadditions of 4-methylene-5-(bromomethylene)-4,5-dihydrothiazole with 2- and 3-bromonaphtha-quinones are highly regiospecific.236... 

It is of note that due to their inherent polarity, 2-trimethylsilyloxybuta-1,3-dienes undergo regiospecific Diels-Alder reactions. As exemplified in Equation Si3.11, hydrolysis of the trimethylsilyl enol ether present in the Diels-Alder product reveals a substituted cyclohexanone. 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

The hitherto unknown l-aza-3-phosphabenzenes are obtained via a regiospecific Diels-Alder reaction with inverse electron demand of 2-trifluormethyl-4-methyl-6//-l,3-oxazin-6-one with phosphaalkynes (81) or phosphaalkenes [Eq. (31)] (82). 

These pyrones undergo Diels-Alder reactions with electron-deficient alkenes with loss of COj and formation of an aromatic ring. Thus reaction with 1,1-dimethoxyethylene (11, 279-281) provides a regiospecific route to methyl salicylates (e.g., 3), which are convertible in several steps into catechol derivatives (4) or by decarbomethoxylation into phenol ethers (5). Similar reactions with vinylene carbonate or 1, 1,2-trimethoxyethylene provide regiospecific routes to phenols, differentially protected derivatives of catechol, resorcinol, or pyrogallol (equation II). 

There are just a few one-pot reactions in which two carbon-carbon bonds are simultaneously formed. One of these is the ancient but exceedingly useful Diels-Alder reaction, for which furans are particularly popular dienes. Consequently there would be nothing unusual about having compound I and methyl vinyl ketone (MVK) coupled in a Diels-Alder cycloaddition mode except for the fact that 2,5-disubstituted furans are known to be reluctant dienophiles. However, the amino group at C-2 considerably increases the reactivity of the furan nucleus as a diene by injecting electron density into the ring s x system. This phenomenon is underscored by the regiospecificity of the cycloadditon. 

Cycloaddition, well known as the Diels-Alder reaction, is a widely-used reaction in the synthesis of organic compounds Including natural products. On the other hand, many possible biosynthetic Diels-Alder constructions from natural sources have been reported [1 - 25]. Such constructions in natural are mostly stereo- and regiospecific, suggesting the pivotal step of the cycloaddltlon reaction in the biosynthesis to be enzymatic. However, the evidence for a biological Diels-Alder reaction is rare. 

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