Diels-Alder reaction acrylic compounds

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

However, none of these compounds can be easily resolved except TM (16) Itself. Me prefer to resolve as early as possible, (page T 94), so It is better to carry out the Diels-Alder reaction with acrylic acid and resolve acid (19) before adding the phenyl group by a Grignard reaction. The benzylic alcohol group in (20) can be taken out by metal-anunonia reduction. Syrithesis ... 

The de Meijere group [63] prepared interesting spiro-compounds containing a cyclopropyl moiety using a combination of a Heck and a Diels-Alder reaction, with bicyclopropylidene 6/1-115 as the starting material. The transformation can be performed as a three-component process. Thus, reaction of 6/1-115, iodobenzene and acrylate gave 6/1-116 in excellent yield. With vinyliodide, the tricyclic compound 6/1-117 was obtained (Scheme 6/1.31). Several other examples were also described. 

Hetero substituted 2-cyclopropylideneacetates are ring-strain activated acrylates, highly reactive dienophiles in Diels-Alder reactions, but also powerful Michael acceptors. The reactivity of these compounds is enhanced by the same strain release in the Diels-Alder cycloadditions as well as in the 1,4-additions, and indeed the borderline between tandem Michael-cyclization and Diels-Alder-type cycloaddition is not well defined in many cases. 

On the basis of available experimental data, it is impossible to choose a definite pathway of elimination of silanol. However, study of silylation of methyl P -nitropropionate (411) with BSA in the presence of trapping agents rigorously proved that silyl nitronate D is initially formed. This compound can be detected in the [3 + 2]-cycloaddition reaction with methyl acrylate product (413). If silylation of AN (411) is performed in the presence of ethyl vinyl ether, a-nitrosoalkene E can be successfully trapped in as heterodiene a Diels-Alder reaction. Dihydroox-azine (414) is formed, and its silylation affords isolable product (415). 

For acrylates, or type I reagents, applied in asymmetric Diels-Alder reactions, several chiral auxiliaries such as menthol derivatives, camphor derivatives,16,3 and oxazolidinones4 are available. Carbohydrate compounds have also been reported as chiral auxiliaries in a recent publication, although the stereoselectivity was not good.5 Here are examples in which asymmetric Diels-... 

Linz et al.6 report the synthesis of enantiomerically pure cyclosarkomycin 6, a stable crystalline precursor of sarkomycin 5. As described in Scheme 5-3, 6 can be obtained from 8, an asymmetric Diels-Alder adduct of (E )-bromoacry-late. (E)-3-bromoacrylate 9a [the acrylate of (R)-pentolactone 11] and 9b [the acrylate of ( S )-A-methyl hydroxyl succinimide 12] undergo TiCL-mediated Diels-Alder reactions giving 10a or 10b, the endo-product, with high diaster-eoselectivity (Scheme 5-4). With the key intermediate 10a in hand, synthesis of compound 6 is accomplished by following the reaction sequence shown in Scheme 5-5. 

Inverse type hetero-Diels-Alder reactions between p-acyloxy-a-phenylthio substituted a, p-unsaturated cabonyl compounds as 1-oxa-1,3-dienes, enol ethers, a-alkoxy acrylates, and styrenes, respectively, as hetero-dienophiles result in an efficient one step synthesis of highly functionalized 3,4-dihydro-2H-pyrans (hex-4-enopyranosides). These compounds are diastereospecifically transformed into deoxy and amino-deoxy sugars such as the antibiotic ramulosin, in pyridines having a variety of electron donating substituents, in the important 3-deoxy-2-gly-culosonates, in precursors for macrolide synthesis, and in C.-aryl-glucopyranosides. 

The enedione (15), a tetracyclic intermediate on a synthetic route to fusidic acid, has been synthesized from the a-methylene-ketone (16) (Scheme 2). The first step, involving a Diels-Alder reaction with a substituted acrylate (17), provides a new versatile annelation procedure. Further modification of (15) by a route worked out on model systems (see Vol. 4, p. 318) afforded the tetracyclic enone (24) with the desired trans-syn-trans geometry (Scheme 3). This compound (24) has also been prepared by degradation of fusidic acid. Attempts to introduce the C-11 oxygen function necessary for the synthesis of fusidic acid have not been very... 

Furo[3,4-(/]pyrimidines are ideally suited for participation in Diels-Alder reactions. The reaction of the derivatives (47) with dienophiles leads to tricyclic compounds of the type (48) <9iJOC245>. There is some selectivity, since methyl acrylate forms only two regioisomeric endo products whilst other dienophiles yield both endo and exo adducts (Equation (13)). 

Another all-carbon Diels-Alder reaction is proposed for the biosynthesis of the indole alkaloids tabersonine 1-6 and catharanthine 1-7 of the Aspidosperma and Iboga family [28-31]. The compounds are formed via strictosidine 1-3, the first nitrogen-containing precursor of the monoterpenoid indole alkaloids, and stemmadenine 1-4, which is cleaved to give the proposed intermediate dehy-drosecodine 1-5 with an acrylate and a 1,3-butadiene moiety (Scheme 1-1). 

Carbonyl compounds have also been used as electrophiles with the intermediate 719 to afford a-allenic alcohols758,783 788 1016 1030,1033-1051 and, after hydrolysis, the corresponding hydroxy enones1034 1037 1051. The chiral acrylate equivalent endo-2-acryloylisoborneol (726), used in metal-free Diels-Alder reactions, has been prepared by reaction of (-El-camphor with compound 7191039 (Scheme 190). 

Tetrasubstituted-l,2,3,4,5,6,7,8-octahydrocarbazoles 1137 were synthesized in 46-90% yields by a novel tandem Diels-Alder reaction in one step from A -benzyl-2,5-dimethyl-3,4-bisacetoxymethylpyrrole 1136 and dienophiles such as maleic anhydride, maleimide, ethyl maleate, fumaronitrile, and ethyl acrylate (Scheme 222) <20000L73>. The 2,3,6,7-tetrasubstituted carbazoles 1138 were then synthesized in 29-87% yields from compound 1137 by oxidation with DDQ. 

About 10 years later the catalytic use of boron derivatives was again investigated by Kaufmann et al. Compounds of the type RBBr2 (R = pinanyl) catalyze the Diels-Alder reaction at -78 °C with low ee (Eq. 3) [4]. Modified isopinocamphenyl dibro-moborane, which has been synthesized since then, gives better results in the reaction of cyclopentadiene and methyl acrylate (Eq. 4) [5]. 

Compound 7 was evaluated as a Diels-Alder catalyst instead of silyl triflate (Sch. 22). As expected from Si NMR measurement, substantial rate acceleration was observed in the Diels-Alder reaction of methyl acrylate with a variety of dienes. 

Since the [6]radialenes are triple-diene systems, it comes as no surprise that they have been used in multiple Diels-Alder reactions. In fact, after a first 1 1 addition with 150, leading to 161, has taken place, the reaction could proceed in two fashions—a linear course of addition leading to a ara-xylylene 162, and an angular route which produces an crf/ic-xylylene intermediate 163 (equation 19)102-103 Whereas for the hexamethyl compound 150 only products formed by the linear route have been detected with a sizeable number of dienophiles (X=X inter alia TCNE, maleic anhydride, benzoquinone, 1,4-naphthoquinone, acrolein, methyl acrylate ), the parent system 4 undergoes threefold Diels-Alder addition in a star-shaped manner leading to 164 with dimethyl acetylenedicarboxylate and to 165 with fumaroyl chloride followed by methanolysis (equation 20). ... 

The first total synthesis of ( )-lycoridine margetine (33), a member of the non-basic alkaloids which possess antimitotic activity has been achieved (Scheme 3). The homoallylic alcohol (26) served as a latent diene in a Diels-Alder reaction with ethyl acrylate to give a diastereomeric mixture of adducts which upon base equilibration and hydrolysis provided the tmns-acid (27). Modified Curtius reaction on (27) afforded the corresponding isocyanate which was cyclized to the lactam (28) in 89% yield by a new method using boron trifluoride etherate. Compound (28) was converted into an N-acetyl derivative which upon basic hydrolysis gave the acid (29). Treatment of (29) with NBS followed by reflux in pyridine solution gave the lactone... 

In the Diels-Alder reaction of trans- 1-methoxybutadiene with ethyl acrylate, either the 1,2- or the 1,3-disubstituted product can be obtained in principle. The 1,3-disubstituted product is thermodynamically more stable (less steric hindrance), but the kinetic product is the 1,2-disubstituted compound. The easiest way to explain this phenomenon is to note that C4 of the diene is nucleophilic, and C2 of the dienophile (i.e., the /1-carbon) is electrophilic. Combination of C4diene with C2dienophiie gives the observed product. 

Prepared by the action of methanolic potassium hydroxide on hexachlorocyclo-pentadiene, the dimethoxy compound is more reactive in Diels-Alder reactions than the 5,5-dichloro derivative and reacts with a number of dienophiles under relatively mild conditions. - The adducts are of interest because they can be aromatized by a simple reaction sequence, as illustrated for the acrylic acid adduct, prepared by... 

The Diels-Alder reaction (diene synthesis) is the addition of compounds containing double or triple bonds (dienophiles) to the 1,4 positions of conjugated dienes with the formation of six-membered hydroaromatic rings. Hydrocarbons most often used in the reaction are 1,3-butadiene, cyclopentadiene, and isoprene, and dienophiles used include maleic anhydride, acrolein, and acrylic acid. The literature on this process is thoroughly reviewed by Alder (1), Kloetzel (59), Holmes (48), and Norton (82). 

Successful polymer supported stereoselective Diels-Alder reaction was performed using immobilized enantiopure 4-(3-hydroxy-4,4-dimethyl-2-oxopyrro-lidin-l-yl)benzoic acid 12 as a chiral auxiliary [15]. The corresponding resin-bound acrylate derivate has been applied as the dienophile 13. Preparation of the precursor started with the combination of pantolactone 10 and the sodium salt of 4-aminobenzoic acid. Conversion into the corresponding benzyl ester followed. The obtained racemate was esterified with (lS)-camphanic acid chloride to a dia-stereomeric mixture to gain the enantiopure compounds by chromatographic separation. After subsequent saponification of the camphanic acid moiety and hydrolysis of the benzyl ester the (R)-enantiomer 11 was coupled to Rink amide resin (Scheme 12.6). 

The classic Diels-Alder reaction continues to be applied to steroidal dienes and has been used to prepare benzene-fused compounds (277) (from 6-methylene testosterone ), and (278) and (279) [from the furano-steroid (217) ] and adducts between A -dienes and methyl acrylate, hexafluorobut-2-yne, dimethylacetylene dicarboxylate, and methyl propiolate have been obtained. In this last reaction the mono-adduct (280) was accompanied by a diadduct, assigned the structure (281), which arises from homo-conjugate Diels-Alder addition and which appears to be the first example of homo-conjugate addition to a substituted bicyclo[2,2,l]heptadiene. The diadduct was also obtained in good yield by treatment of the mono-adduct with more methyl propiolate. 

Nitrile, azo, and nitroso groups, and even the oxygen molecule, take part in such reactions, and acetylenic triple bonds in particular confer reactivity as philodiene. As for dienes, so for philodienes the reactivity depends on the constitution. Activating groups particularly favor addition. The most reactive components include <%,/ -unsaturated carbonyl compounds such as acrolein, acrylic acid, maleic acid and its anhydride, acetylenedicarboxylic acid, p-benzo-quinone and cinnamaldehyde, as well as saturated nitriles and <%,/ -unsaturated nitro compounds. Tetracyanoethylene also reacts with dienes.41,42 Conjugation of the double bond to an active group is not absolutely essential for a philodiene, for dienes add under certain conditions also to philodienes with isolated double bonds examples of the latter type are vinyl esters and vinyl-acetic acid. Ketenes do not undergo the Diels-Alder reaction with dienes, but instead yield cyclobutanone derivatives 43,44... 

Most of the classical dienes are hydrocarbons, like cyclopentadiene. butadiene, anthracene, 9,10-dimethylanthracene, isoprene, 2,3-dimethylbutadiene. For dienes of this kind it is generally true that electrophilic dienophiles are the most reactive, and actually acrylic derivatives, maleic anhydride, p-benzo-quinone and similar compounds have found a large use as dienophiles both for preparative purposes and for kinetic studies. The latter demonstrated quantitatively the importance of electronegative groups on the dienophiles, and conversely of electron-releasing substituents on the diene, in order to accelerate such type of Diels-Alder reaction. It was also realised later that Diels-Alder additions with inverse electron demand , that is between electrophilic dienes and nucleophilic dienophiles, do occur . ... 

---