Ketones, methyl vinyl 3 + 2 cycloaddition reactions

Similar cycloaddition reactions were observed with methyl vinyl sulfone (48) and )3-nitrostyrene (48,51). Methyl vinyl ketone, on the other hand, is reported to give dihydropyrans as the initial products (50,52,53). Thus (16) on reaction with methyl vinyl ketone at room temperature for 12 hr gave a 60% yield of 2-dimethylamino-3,3,6-trimethyl-3,4-dihydro-2H-pyran (59). 

The initial product formed when methyl vinyl ketone is mixed with an enamine [such as N,N-dimethylisobutenylamine (10)] is the dihydropyran (11) from a 1,4 cycloaddition (ll,20a,20b). The chemical reactions that the dihydropyran undergoes indicate that it is readily equilibrated with the cyclobutane isomer 12a and zwitterion 12 (11). Treatment of adduct 11 with phenyllithium gives cyclobutane 13, possibly via intermediate 12a (11). 

Heterocyclic enamines often undergo two-step 1,3 cycloaddition with methyl vinyl ketone. This involves electrophilic attacks by an olefinic carbon and by a carbonyl carbon (24,25). For example, 1,2-dimethyl-Zl -pyrroline (14), when treated with methyl vinyl ketone, produces 1,6-dimethyl-2,3,4,5-tetrahydroindole (15) (24). The requirement which must be met so that this type of cyclization reaction can take place is that the a position of the heterocyclic enamine be carbon substituted. This provides... 

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

Dihydropyrans have been produced by the 1,3 cycloaddition of methyl vinyl ketone (77) or acrolein (29-J7) with enamines (see Section II.A.2). S-Lactones have been formed as a side product in the reaction of dimethyl ketene with enamines (77), and as the primary products in the reaction of excess ketene with enamines derived from ketones (75) (see Section II.A.4). 

In a more recent publication the same group mentions that Ag(I) salts in combination with chiral phosphine ligands can catalyze the 1,3-dipolar cycloaddition involving the azomethine precursor 64b and methyl vinyl ketone (Scheme 6.43) [87]. The reaction, which presumably also required a stoichiometric amount of the catalyst, proceeds to give 65b in a good yield with 70% ee. 

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. 

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]. 

Indium trichloride [30] and methylrhenium trioxide [31] catalyze the aqueous Diels-Alder reaction of acrolein and acrylates with cyclic and open-chain dienes. Some examples of the cycloaddition of methyl vinyl ketone with 1,3-cyclohexadiene are reported in Scheme 6.18. MeReOs does not give satisfactory yields for acroleins and methyl vinyl ketones with substituents at the jS-position and favors the self-Diels-Alder reaction of diene. 

In an attempt to prepare new diprenorphine analogs, Linders, in one of the first examples of microwave-induced organic reactions, reported the reaction between methyl vinyl ketone and 6-demethoxy-/J-dihydrothebaine (48) [53], The Diels-Alder reaction, when performed under classical conditions, led to extensive polymerization of the dienophile. A dramatic improvement was achieved when the cycloaddition was conducted in a modified microwave oven at the reflux temperature of methyl vinyl ketone. By use of these conditions adducts 49 and 50 were obtained in a 3 2 ratio, according to HPLC (Scheme 9.12). 

Some new observations were published on the peculiar reactivity of the phenyloxazolopiperidine 166 which acts as an equivalent of an enamine, reacting with methyl vinyl ketone in a Michael reaction and with diethyl acetylenedicarboxylate in a [2+2] cycloaddition reaction <00JOC3209>. 

In this approach, the SENA skeleton is assembled from nitroalkene (42) and nucleophile 56.With the exception of two examples (entries 1 and 2 in Table 3.2), the reaction does not stop at SENA 51, which either undergoes intramolecular cyclization through [3 + 2]-cycloaddition to give fused heterocycles (as a rule after elimination of trimethylsilanol) (198-200) or is involved in [3+ 2]-cycloaddition with specially added methyl vinyl ketone or methyl acrylate to form (after elimination of silanol) substituted isoxazolines in rather high yields (201). 

Such a reaction was utilized to promote the anionic [3 + 2]-cycloaddition [103], With KCN as the catalyst, the reaction of propadienyl phenyl sulfone with methyl vinyl ketone provided 206 (E = COCH3) in 80% yield as the only product. The reaction is stepwise since l-(3 -oxobutyl)-l,2-propadienyl phenyl sulfonyl 209 was formed together with 206 (E = COMe) in a 1 1 ratio when lithium benzenesulfmate was used as the promoter. 

In subsequent studies, methyl vinyl ketone (2.0 mmole) was chosen as the dienophile so as to determine the combined effect of the ionic liquid (2 mL) and the Lewis acids (0.2 and 0.5 wt%) upon the yield and selectivity. Without the Lewis acid catalyst, this system demonstrated a 52% conversion of the cyclopentadiene (2.2 mmol) in 1 h with the endojexo selectivity being 85/15. The cerium triflate-catalyzed reaction was quantitative in 5 min and the endo. exo selectivity was very good for this experiment as well (94 6, endo. exo). Also with the scandium or yttrium salts tested, reactions came to completion in a short time with high stereo-selection. Cerium, scandium and yttrium triflates are strong Lewis acids known to be quite effective catalysts in the cycloadditions of cyclopentadiene with acyclic aldehydes, ketones, quinones and cycloalkenones. These compounds are expected to act as strong Lewis acids because of their hard character and the electron-withdrawing triflate group. On the other hand, reaction times of 1 hour were required for... 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

Scheme 1.64). The Ag(I)-mediated cyclization afforded dipole 306 for 1,3-dipolar cycloaddition with methyl vinyl ketone to yield adducts 307 and the C(2) epimer as a 1 1 mixture (48%). Hydrogenolytic N—O cleavage and simultaneous intramolecular reductive amination of the pendant ketone of the former dipolarophile afforded a mixture of alcohol 308 and the C(6) epimer. Oxidation to a single ketone was followed by carbonyl removal by conversion to the dithiolane and desulfurization with Raney nickel to afford the target compound 305 (299). By this methodology, a seven-membered nitrone (309) was prepared for a dipolar cycloaddition reaction with Al-methyl maleimide or styrene (301). 

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