Cycloadditions with Dienophiles

Vogel has developed 7-oxanorborn-5-en-2-one 2 and its derivatives as versatile alternative synthons for sugar chirons hence these substrates have been coined naked sugars. Several reviews summarizing this work have appeared [11]. The key cycloaddition in the synthesis is a Diels-Alder reaction between 

Enantiomerically enriched products can also be obtained by employing a dienophile bearing a chiral controller group [13]. For example, the use of the camphanate ester derivative (S)-3b (also available in the (R) form) in the cycloaddition with furan gave a 29% yield of diastereomer 4 b after purification, along with other endo and exo isomers, Eq. 2. Saponification afforded the chiral ketone (+)-2. Reactions of 4b and 2 have been reported to occur with high regio-and stereocontrol (vide infra). 

Koizumi observed a diastereoselective cycloaddition between furan and chiral vinyl sulfoxides 6 [15]. While the analogous p-tolylsulfinyl acrylates were completely unreactive in this reaction, the 2-pyridyl (Py) substituent signifi- 

An extremely efficient and high yielding catalytic asymmetric Diels-Alder reaction of furan was reported by Corey [17]. In the presence of 10 mol% of oxazaborolidinone 7, Fig. 2, the cycloaddition between furan and 2-bromoacro-lein proceeded to give the exo oxanorbornene derivative 8 in excellent yield and 92% ee, Eq. 5. Compound 8 can be efficiently converted to oxanorbornenone (+)-2, which is otherwise obtained by the Vogel methodology. 

A methylsulfido substituent on the furan significantly enhances its reactivity toward dienophiles. Therefore, cycloadditions of 3-methylthiofuran proceeds even with monoactivated olefins to give predominantly the endo adducts, Eq. 6 [18]. Moreover, chiral titanium catalysts generated in situ from (z-PrO)2TiCl2 and tartrate derivative 9, Fig. 2, induce cycloaddition with 3-acryloyl-l,3-oxazo-lidin-2-one with good enantioselectivity and in excellent yield, Eq. 7. 

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The diene undergoes Diels-Alder cycloaddition with dienophiles. Polyimides have been synthesized from various imide-containing benzocyclobutenes and dienophiles (83—85). 

Reactivity of 1-azadienes 87 and the regioselectivity and stereoselectivity of the cycloadditions with dienophiles 88 are strongly dependent on the type of... 

Pummerer-type dehydration of the sulfoxide 408 using acetic anhydride results in efficient formation of the 1,3-dipolar compound 409 which is able to undergo cycloaddition with dienophiles to generate tricyclic compounds such as 410 in good yield (Scheme 31) <2000T10011>. 

Compounds of the general structure 284 undergo a cycloaddition with dienophiles (Scheme 66) <1991S543> and those with general structure 285 react with dielectrophiles to give dihydrothiazines (Equation 88) <1998T2459>. 

Fluorinated dienes have been described, though again, the incidence is rare. Treatment of an a,/ -unsaturated-a-fluoroaldehyde with chlorotrimethyl silane afforded [369] the l-trimethylsilyloxy-2-fluorobutadiene which underwent [4 + 2] cycloadditions with dienophiles, though more slowly than its non-fluori-nated counterpart, and with lower regioselectivity (Eq. 148). 

The hetero-Diels-Alder reaction continues to be a popular method of producing the tetrahydroquinoline ring structure. The generation of o-azaxylylene allows for the subsequent cycloaddition with dienophiles to produce the corresponding quinoline ring structure (Scheme 73) <1998H(48)1103, 1998JHC467>. 

Cycloadditions with homophthatic anhydride Homophthalic anhydride can undergo thermal cycloaddition with dienophiles with loss of carbon dioxide, but the yields are generally low. The reaction can proceed at room temperature with dramatic improvement of the yield if the anhydride is first converted into the sodium salt (NaH) or lithium salt (LDA). The cycloaddition provides a regioselective route to peri-hydroxy polycyclic compounds. 

Each of the three systems has a strong tendency for cycloaddition with dienophiles across the 1- and 3-positions, thereby gaining the stabilising contribution of a complete benzene ring, isobenzofuran itself, for example, reacts instantly at 0 °C with maleic anhydride. Isobenzofuran has been dubbed the most reactive isolable diene . More typically, the synthesis of one of these non-isolable, or extremely reactive systems, is immediately followed by a trapping with a dienophile, so that discussion of synthesis must inevitably involve discussion of the product cycloaddition chemistry. 

Azabutadienes, e.g. (20), variously generated,undergo cycloaddition with dienophiles to form, after aromatization, substituted pyridines, e.g. (21). With unsymmetrical dienophiles such as acrylonitrile, the reaction is regiospecific (Scheme 10). 

Cyclopentadiene is a very reactive diene and exists as its dimer that needs to be cracked (retro-Diels-Alder reaction) to prepare the diene. Cycloaddition with dienophiles forms bridged compounds of the bicyclo[2.2.1]heptane series. The reaction of cyclopentadiene with mono-and cw-disubstituted alkenes could give rise to two stereochemically distinct products, the endo- and ejco-bicyclo[2.2.1]heptene derivatives. It is found in practice, however, that the endo isomer predominates. 

Reactions of dienes containing optically active auxiliary groups have not been so widely studied as those of chiral dienophiles. There are, however, examples of the use of various chiral auxiliaries attached to either C-1 or C-2 of the diene. The 1-substituted diene 130, derived from mandelic acid, undergoes cycloaddition with dienophiles in the presence of boron trifluoride or boron triacetate (3.94). With the dienophile juglone, the adduct 131 was formed with virtually complete asymmetric induction. The absolute configuration of the product corresponds to reaction of the diene in the conformation in which one face of the diene is shielded by the phenyl substituent. 

Each of the three systems has a strong tendency for cycloaddition with dienophiles across the 1- and 3-positions, thereby gaining the stabilising contribution of a complete benzene ring isobenzofuran itself, for example, reacts instantly at 0°C with maleic anhydride. ... 

Diels-Alder Reactions. 2-Trimethylsilylmethyl-1,2-butadiene and 2-trimethylstannylmethyl-1,3-butadiene undergo facile cycloaddition with dienophiles (eq 11). The reactions of 2-trimethylsilylmethyl- and 2-trimethylstannylmethyl-1,3-butadiene with unsymmetrical dienophiles give the so-called para product predominantly, and the selectivity is much higher in the reactions with 2-trimethylsilylmethyl- and 2-trimethylstarmylmethyl-1,3-butadiene compared to reactions with isoprene. The paralmeta ratios in the reactions with methyl acrylate (eq 12) are 70/30 (X = H), 84/16 (X = SiMej), and 91/9 (X = SnMes)."... 

A Pd-catalyzed method for generating indole-2,3-QDMs 84 from a-phosphonoenecarbamates 83 via the intramolecular Heck reaction was developed by Fuwa and Sasaki [41]. The resulting indole-2,3-QDMs could readily be trapped in situ by such electron-deflcient dienophiles as methyl acrylate, acrylonitrile, and A-methylmaleimide to afford the respective tetrahydrocarbazoles 85 (Scheme 28.29). They also developed an efficient approach to indole-2,3-QDMs from Af-(o-iodoaryl)allenamides 86 under the palladium catalysis, being utilizable for [4 -I- 2] cycloaddition with dienophiles [42]. 

As another example leading to novel conformationally restricted peptidomimetics, a Pd-catalysed enyne cycloisomerization was described as a route to macrocyclic diene structures (119, Figure 11.13, site of ring closure and palladium species indicated). Subsequent [4+2] cycloadditions with dienophiles then gave the target molecules. An interesting application of the use of palladium catalysis in macrocyclization was reported by Barnickel and... 

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