Cycloaddition reactions heterodienophiles

The most frequently encountered, and most useful, cycloaddition reactions of silyl enol ethers are Diels-Alder reactions involving silyloxybutadicncs (Chapter 18). Danishefsky (30) has reviewed his pioneering work in this area, and has extended his studies to include heterodienophiles, particularly aldehydes. Lewis acid catalysis is required in such cases, and substantial asymmetric induction can be achieved using either a chiral lanthanide catalyst or an a-chiral aldehyde. 

The P-nitroso phosphine oxide 406 behaves as an N-O heterodienophile and reacts with the 1,3-diene part of the molecule in a cycloaddition reaction to form the 2,4 ,5,6,7,8-hexahydro-8-phenyl-[l,2]azaphosphorino[l,6-3][l,2]oxa-zine 8-oxide 407 containing an stereogenic cyclic phosphorus atom (Scheme 64). 31P NMR spectroscopy shows one single peak indicating the formation of only one diastereomer <2002JOG6174>. 

The formation of heterocycles by cycloaddition reactions of conjugated dienes is the subject of this chapter. Almost the entire account is devoted to the Diels-Alder reaction of dienes with heterodienophiles to yield six-membered ring compounds (equation 1). Many such reactions have been reported and there is a plethora of reviews. Somela p are general others are cited at appropriate places in the text. This account is highly selective, concentrating on recent work with particular regard to the stereochemistry of these processes. 

Also propiogeninic type macrolide moieties should be accessible via this inverse type hetero-Diels-Alder methodology. This was recently exhibited starting from cis-propenylether as heterodienophile (Schmidt, R.R. Haag-Zeino, B. Hoch, M. Liebigs Ann. Chem., in press). In a highly endo-selective cycloaddition reaction and in subsequent diastereoselective transformations of the methyl substituted dihydropyran obtained a 2,4-dimethyl-... 

The reactivity of the benzo analogue of compound 41, that is, 2//-naphtho[l,2-4]thiete 47, has also been studied. Cycloaddition reactions with dienophiles or heterodienophiles performed in boiling toluene yielded naphtho-condensed sulfur heterocycles (Scheme 5) <1998JHC1505>. 

The HDA reaction allows for rapid access to chiral six-membered heterocyclic structures that serve as valuable intermediates in organic synthesis. The first highly enantioselective HDA reaction promoted by a chiral hydrogen bond donor was reported from the Rawal laboratory. While investigating the cycloaddition reactions of amino-siloxy diene 115, it was observed that this diene was exceptionally reactive to heterodienophiles, and underwent HDA reactions with various aldehydes at room temperature, even in the absence of any added catalyst (Scheme 6.14). Subsequent treatment of the intermediate cycloadducts (116) with acetyl chloride afforded the corresponding dihydro-4-pyrones (117) in good overall yields [101]. Further studies of this reaction revealed a pronounced solvent effect,... 

Hetero Diels-Alder cycloaddition reactions, synthesis of natural heterocyclic products by, 42, 245 Heterodienophiles, new, heterocyclic synthesis using, 55, 1 Hilbert-Johnson reaction of 2,4-... 

Hetero-Diels-Alder reactions performed with trifluoromethyl-substituled heterodienes or with trifluoromcthyl-substituted heterodienophiles have resulted in the synthesis of a large number of fluoro-heterocyclic compounds. Ketones, thioketones, imincs, nitriles, and their parent a,/3-unsaturated systems have been studied in cycloaddition reactions. Cycloadditions are regioselec-tive. An interesting aspect is the competition with ene-type reactions, aldol reactions and, depending on the partners, with [2 + 2]-cycloaddition reactions. 

Sulfines, which are thiocaibonyl 5-oxides, have been used many times as heterodienophiles. As with thioaldehydes, the development of this field has been limited more by the availability of these often unstable species rather than by problems with the Diels-Alder chemistry. It should be noted that sulfines can exist as configurationally stable ( )- or (Z)-isomers and this stereochemistry can play a role in the outcome of the cycloaddition reactions. 

Examples of the 477- participation of simple a,/3-unsaturated carbonyl compounds in Diels-Alder reactions and their application to the total syntheses of natural products are summarized in Table 7-1. Reports of simple a,/3-unsaturated carbonyl compounds participating in [4 + 2] cycloadditions with heterodienophiles have been detailed [Eq. (9)].73b 75... 

Lewis acid-proton acid combination such as BF3 0Et2-CF3C02H was found to be highly effective for the activation of imines as heterodienophiles in Diels-Alder cycloaddition reactions, and under these conditions compound (189 X = O) was obtained in excellent yield <85JMC1756, 87TL2103>. 

The emphasis in this work is on the scope and preparative synthetic utility of the hetero Diels-Alder reaction. No attempt has been made to carefully define or delineate the important mechanistic questions, many of which are as yet unanswered, of the various [4 -I- 2] cycloaddition reactions other than to try to provide a rationale for the facility with which the cycloadditions proceed and to provide a basis for the stereo- and regio-chemical observations. We have purposely excluded reactions of singlet oxygen as a dienophile, since extensive surveys are available elsewhere. Many miscellaneous heterodienophiles and heterodienes have not been covered if in our opinion they are not of general synthetic value. A comprehensive treatment of all recorded hetero [4 + 2] cycloadditions is beyond the scope of this monograph. However, we do hope to provide a broad survey of this reaction type as it exists today in order to furnish a foundation for continued development. 

For a cycloaddition reaction of a 1,2,4,5-tetrazine 1 with a heterodienophile to proceed successfully, the latter must be activated with an electron-donating group. In this sense, thioimidates, imidates, and amidines 335 proved to be reactive heterodienophiles in the inverse Diels-Alder reactions with 1,2,4,5-tetrazines 1. The reaction proceeds via the initial formation of the bicyclic adduct 336, followed by the loss of a nitrogen molecule to form the dihydro cycloadduct 337, and final aromatization by the loss of a thioalkoxy, alkoxy, or amino group to form the final 1,2,4-triazines 338 (Scheme 82). 

Hetero Diels-Alder cycloaddition reactions are of great importance in organic chemistry for the synthesis of six-membered heterocyclic ring systems. " In the past heterodienophiles and -dienes with one or more oxygen, nitrogen or sulfur atoms have been examined in thermal and Lewis acid-catalyzed reactions. " ... 

Different kinds of diene and dienophile are used in the Diels-Alder reactions. Dienes and dienophiles with a heteroatom such as N, O, or S in their Jt systems are known as heterodienes and heterodienophiles, and their cycloaddition reactions are called the hetero-Diels-Alder reactions. Some highly reactive dienes and dienophiles used in Diels-Alder reactions are listed in Table 3.4. 

A review of the cycloaddition reactions of o-benzoquinones as carbodiene, heterodiene, dienophile, or heterodienophile has been published. In the Diels-Alder reaction of furans with masked o-benzoquinones (145), the furans unexpectedly behaved as dienophiles to yield cycloadducts (146) (Scheme 56). Masked benzoquinones behave as dienes which undergo Diels-Alder reactions with electron-rich dienophiles such as enol ethers and thienol ethers.The asymmetric Diels-Alder reactions of 5-substituted and 5,6-disubstituted (S)-2-(p-tolylsulflnyl)-l,4-benzoquinones with cyclopentadiene and fran -piperylene show complete regio- and jr-facial selectivities. The hetero-Diels-Alder reactions of o-benzoquinones with tetracyclone produce cyclopenta[I ][l,4]benzodioxinone derivatives in high yield. 

These pentacyclic products arise from aniline-derived iminium ions functioning as dienes rather than heterodienophiles in two sequential [4+2] cycloaddition reactions with cyclopentadiene. It is noteworthy that use of the preformed Schiff base under non-aqueous conditions leads to the formation of tricyclic tetrahydroquinoline derivatives wherein one cyclopentene unit is incorporated [5]. 

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