Diels-Alder reactions with methyl vinyl ketone

Linders, J.T.M., Briel, P., Fog, E., Lie, T.S. and Maat, L., Chemistry of opium alkaloids, Part XXVIII preparation of 6-demethoxy-N-formyl-N-northebaine and its Diels-Alder reactions with methyl vinyl ketone and nitroethene novel 8-nitro-substituted 6a,14a-ethenoisomorphinans and 6 3,14 3-ethenomorphinans, Rec. 

The synthesis starts from thebeine, which is subjected to a Diels-Alder reaction with methyl vinyl ketone and then reacted with n-butylmagnesium chloride. Finally, in a nucleophilic substitution, the methoxy-group is replaced by hydroxy. 

Tire results of a study of the effect of these catalysts on the model Diels-Alder reaction of methyl vinyl ketone (4.8) with cyclopentadiene (4.6) are summarised in Table 4.1... 

Rare-earth-metal triflates are efficient catalysts in Diels-Alder reactions, and Sc(OTf)3 is clearly more effective than Ln(OTf)3 as a catalyst.45,53-55 In the presence of 10mol.% Y(OTf)3 or Yb(OTf)3, only a trace amount of the adduct was obtained in the Diels-Alder reaction of methyl vinyl ketone (MVK) with isoprene. In contrast, the reaction proceeded smoothly to give the adduct in 91% yield in the presence of 10mol.% Sc(OTf)3 (Scheme 13).45 Sc(OTf)3 has also proved to be an efficient catalyst for the Diels-Alder reaction of imines (aza Diels-Alder reactions).56,57... 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

Entries 6-10 deal with the Diels-Alder reactions of methyl vinyl ketone with furan and also include the use of AICI3 (entry 6), high pressure (entry 7) and Cu ion-exchanged Y-zeolite (entry 9). This series, however, displayed only modest exo selectivities. The highest product ratio (258 Y = 0)/(259 Y = O) = 20 80 was found on adsorption of the educts on dry Si02 MgO (entry 10). 

Scheme 61 and Table 10 illustrate the influence of SnCU or solid supports on the Diels-Alder reactions of methyl vinyl ketone or acrolein with isoprene. Apart from the reaction rate, the regiochemical control was substantially increased, e.g. from 59 41 to 99.5 0.5 (entries 5/7) in favor of the para products (260). 

A total synthesis of adaline (550) has been performed (73BSB699). The vinyl ketone 547 was submitted to hetero Diels-Alder reaction with methyl vinyl ether to yield the dihydropyran derivative 548 in 60% yield. Acid hydrolysis of 548 produced the keto aldehyde 549. Finally, a Mannich reaction involving... 

A new synthesis of racemic oleuropeic acid (216) starts with the known Diels-Alder reaction between methyl vinyl ketone and chloroprene, yielding the chloro-ketone (217). The acid function is introduced by exchanging the chlorine atom for lithium, followed by conversion into the aldehyde with dimethylformamide, and the additional methyl group is put in with a Grignard reaction (Scheme 16). ... 

Diels-Alder reaction of methyl vinyl ketone (MVK) with iso-prene, the adduct is obtained in 91% yield in the presence of 10 mol % Sc(OTf)3, while 10 mol % Y(OTf)3 or Yb(OTf)3 gives only a trace amount of the adduct.Sc(OXf)3-catalyzed Diels-Alder reactions generally provide high yields with high endo selectivities. The present Diels-Alder reaction even proceeds in aqueous media. Thus, naphthoquinone reacts with cyclopenta-diene in H2O-THF (9 1) at room temperature to give the corresponding adduct in high yield (100% endo) (eq 16). Sc(OTf)3 also serves as an effective catalyst for Diels-Alder reactions in supercritical carbon dioxide (sc C02). ... 

The catalytic effect of thiourea derivative 26 (a bidentate hydrogen-bond donor) was investigated in the Diels-Alder reaction of methyl vinyl ketone (27) with cyclopentadi-ene (5) in cyclohexane (that has negligible interactions with the solutes), chloroform (a weak hydrogen-bond donor), and in water (a high polar solvent) to give 5-norbornene-2-methylketone (28) (Table 5.2). 

Table 5.2 Diels-Alder reactions of methyl vinyl ketone (27) with cyclopentadiene (5) catalyzed by thiourea derivative 26 in water and organic solvents...

To overcome poor Lewis acidity of Li" ", interesting bimetallic dual activation system has been developed (Scheme 3.7) [25]. Two Li" ", oriented at an appropriate distance, coordinate to two oxygen lone pair of carbonyl group and induce greater activation. Bidentate lithium Lewis acid (3) promotes Diels-Alder reaction of methyl vinyl ketone with cyclopentadiene to provide the cycloadduct in 71% yield. 

Since both oxidative splitting of the double bond and aldol condensation represent reliable and general reactions, their sequence serves as an efficient route for the transformation of readily available cyclohexene systems e.g. formed via the Diels-Alder reaction or Robinson annulation) into functionalized cyclopentene derivatives. This standard operational mode is extensively used in total syntheses. One of the numerous examples, the synthesis of helminthosporal 463, the sesquiterpenoid toxin of fungi, is shown in Scheme 2.150. In the initial phases of the synthesis, commercially available (—)-carvomenthone 464 was transformed into 465 via Michael reaction with methyl vinyl ketone to give 466 and subsequent intramolecular aldol condensation. 

Figure 1.2. Endo and exo pathway for the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone. As was first noticed by Berson, the polarity of the endo activated complex exceeds that of the exo counterpart due to alignment of the dipole moments of the diene and the dienophile K The symmetry-allowed secondary orbital interaction that is only possible in the endo activated complex is usually invoked as an explanation for the preference for endo adduct exhibited by most Diels-Alder reactions.

The ability of 1,2 (or l,6)-dihydropyridines to undergo a Diels-Alder reaction with dienophiles such as methyl vinyl ketone, methyl acrylate, and acrylonitrile has been utilized in the synthesis of polyfunctional isoquinuclidine as a key intermediate in the synthesis of aspidosperma- and iboga-type alkaloids (66JA3099). 

For example, the Diels-Alder reaction of A-benzyl-3-carboxamido-1,6-dihydro-pyridine (14a) andlV-benzyl-3-cyano-l,6-dihydropyridine (14b) with methyl vinyl ketone yielded isoquinuclidines 15a and 15b, respectively, which can be converted into ibogamine alkaloid (16). 

It is believed that clay minerals promote organic reactions via an acid catalysis [2a]. They are often activated by doping with transition metals to enrich the number of Lewis-acid sites by cationic exchange [4]. Alternative radical pathways have also been proposed [5] in agreement with the observation that clay-catalyzed Diels-Alder reactions are accelerated in the presence of radical sources [6], Montmorillonite K-10 doped with Fe(III) efficiently catalyzes the Diels-Alder reaction of cyclopentadiene (1) with methyl vinyl ketone at room temperature [7] (Table 4.1). In water the diastereoselectivity is higher than in organic media in the absence of clay the cycloaddition proceeds at a much slower rate. 

Table 4.1 Diels-Alder reactions of cyclopentadiene (1) with methyl vinyl ketone catalyzed by Fe(II)-K-10 montmorillonite in various solvents...

The Diels-Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile are accelerated when carried out in water in the presence of jS-CD but are slower with a-CD [65a] (Scheme 4.16). This is in agreement with the observation that the transition states of these cycloadditions fit into the hydro-phobic cavity of P-CD but not in the smaller a-CD cavity. 

Rideout and Breslow first reported [2a] the kinetic data for the accelerating effect of water, for the Diels Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile and the cycloaddition of anthracene-9-carbinol with N-ethylmaleimide, giving impetus to research in this area (Table 6.1). The reaction in water is 28 to 740 times faster than in the apolar hydrocarbon isooctane. By adding lithium chloride (salting-out agent) the reaction rate increases 2.5 times further, while the presence of guanidinium chloride decreases it. The authors suggested that this exceptional effect of water is the result of a combination of two factors the polarity of the medium and the... 

The aqueous medium also has beneficial effects on the diastereoselectivity of the Diels-Alder reactions. The endo addition that occurs in the classical cycloadditions of cyclopentadiene with methyl vinyl ketone and methyl acrylate is more favored when the reaction is carried out in aqueous medium than when it is performed in organic solvents (Table 6.4) [2b, c]. 

An ab initio MO calculation by Jorgensen revealed enhanced hydrogen bonding of a water molecule to the transition states for the Diels-Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile, which indicates that the observed rate accelerations for Diels-Alder reactions in aqueous solution arise from the hydrogenbonding effect in addition to a relatively constant hydrophobic term.7,76 Ab initio calculation using a self-consistent reaction field continuum model shows that electronic and nuclear polarization effects in solution are crucial to explain the stereoselectivity of nonsymmetrical... 

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