Lithium Diels-Alder reactions

In 1990 Grieco introduced a 5 molar solution of lithium perchlorate as a new medium for the Diels-Alder reaction that is capable of inducing not only an improvement of the rate but also of the endo-... 

Breslow supported this suggestion by demonstrating that the cycloaddition can be further accelerated by adding anti cliaotropic salts such as lithium chloride, whereas chaotropic salts such as guanidium chloride led to a retardation " "" ". On the basis of these experiments Breslow excluded all other possible explanations for the special effect of water on the Diels-Alder reaction " . 

Other methods for the preparation of cyclohexanecarboxaldehyde include the catalytic hydrogenation of 3-cyclohexene-1-carboxaldehyde, available from the Diels-Alder reaction of butadiene and acrolein, the reduction of cyclohexanecarbonyl chloride by lithium tri-tcrt-butoxy-aluminum hydride,the reduction of iV,A -dimethylcyclohexane-carboxamide with lithium diethoxyaluminum hydride, and the oxidation of the methane-sulfonate of cyclohexylmethanol with dimethyl sulfoxide. The hydrolysis, with simultaneous decarboxylation and rearrangement, of glycidic esters derived from cyclohexanone gives cyclohexanecarboxaldehyde. 

Kobayashi et al. have reported the use of a chiral lanthanide(III) catalyst for the Diels-Alder reaction [51] (Scheme 1.63, Table 1.26). Catalyst 33 was prepared from bi-naphthol, lanthanide triflate, and ds-l,2,6-trimethylpiperidine (Scheme 1.62). When the chiral catalyst prepared from ytterbium triflate (Yb(OTf)3) and the lithium or sodium salt of binaphthol was used, less than 10% ee was obtained, so the amine exerts a great effect on the enantioselectivity. After extensive screening of amines, ds-1,2,6-... 

Shibasald et al. reported that lithium-containing, multifunctional, heterobimetallic catalysts such as LaLi3tris((l )-6,6 -dibromobinaphthoxide) 35, with moderate Lewis acidity in non-polar solvents, promote the asymmetric Diels-Alder reaction to give cycloadducts in high optical purity (86% ee) [53] (Scheme 1.67). The lithium... 

A study of the Diels-Alder reaction was carried out by Earle et al. [42]. The rates and selectivities of reactions between ethyl acrylate (EA) and cyclopentadiene (CP) in water, 5 m lithium perchlorate in diethyl ether (5 m EPDE), and [BMIM][PE(3] were compared. The reactions in the ionic liquid [BMIM][PE(3] were marginally faster than in water, but both were slower than in 5 m EPDE [42, 43] (see Table 5.1-1 and Scheme 5.1-18). It should be noted that these three reactions give up to 98 % yields if left for 24 hours. The endo. exo selectivity in [BMIM][PE(3] was similar to that in 5 M EPDE, and considerably greater than that in water (Table 5.1-1). 

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

The Diels-Alder reaction of nonyl acrylate with cyclopentadiene was used to investigate the effect of homochiral surfactant 114 (Figure 4.5) on the enantioselectivity of the reaction [77]. Performing the reaction at room temperature in aqueous medium at pH 3 and in the presence of lithium chloride, a 2.2 1 mixture of endo/exo adducts was obtained with 75% yield. Only 15% of ee was observed, which compares well with the results quoted for Diels-Alder reactions in cyclodextrins [65d]. Only the endo addition was enantioselective and the R enantiomer was prevalent. This is the first reported aqueous chiral micellar catalysis of a Diels-Alder reaction. 

Among special chemical methods that facilitate the Diels-Alder reaction can be included the temporary metal connection strategy [101] that is illustrated in Table 4.27. Si, Mg and A1 are used as temporary connectors of diene and dienophile moieties. The cycloaddition occurs easily due to its intramolecular nature and because the dienophilic component of reagent is now formally a vinyl carbon ion (i.e. a vinyl carbanion in 154 with M = AlEt ). Thus the metal-tethered 154, prepared from lithium alkoxide of 153 with the suitable metal vinyl halide, gives, by heating, the cycloadducts 156 and 157, through the... 

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... 

Lithium perchlorate in nitromethane (LP-NM) is sometimes a more effective reaction medium than LP-DE for certain Diels-Alder reactions. The cycloaddition of 2,3-dimethylbutadiene with nitrostyrenes (Scheme 6.24) occurs with low... 

A convenient alternative to LP-DE is lithium trifluoromethanesulfonimide (LiNTf2) in acetone or diethyl ether (LT-AC, LT-DE). Representative examples are the Diels-Alder reactions of citraconic anhydride with cyclopen-tadiene and of dimethyl acetylenedicarboxylate with isoprene [47] (Scheme 6.26). 

Table 6.8 reports the relative reaction rates of Diels-Alder reactions of 2,5-dimethylbenzoquinone with tran -piperylene in different lithium salt solutions. The data show that the reaction rate depends on the concentration of LT and that in 4.0m LT-AC and 4.0m LT-DE the rate accelerations are comparable to that exhibited in 5.0m LP-DE and 5.0m LP-AC. 

Acid catalyzed intramolecular Diels-Alder reactions in lithium perchlorate-diethyl ether acid promoted migration of terminal dienes prior to [4 + 2] cycioaddition in conformationally restricted substrates [101]... 

Acid catalyzed ionic Diels-Alder reactions in concentrated solutions of lithium perchlorate in diethyl ether [43]... 

Lithium catalyzed hetero-Diels-Alder reactions. Cyclocondensation of N-protected ot-amino aldehydes with 1-methoxy-3-fert-butyldimethylsilyloxybutadiene in the presence of lithium perchlorate [104]... 

Diels-Alder reactions of quinones generated in situ by electrochemical oxidation in lithium perchlorate-nitromethane [105]... 

Catalysis by lithium perchlorate in dichloromethane Diels-Alder reactions and 1,3-Claisen rearrangements [100]... 

Lithium trifluoromethanesulfonimide in acetone or diethyl ether as a safe alternative to lithium perchlorate in diethyl ether for effecting Diels-Alder reactions. Unexpected influence of the counterion on exo/endo selectivity [47]... 

Keywords imines derived from formylphosphonate undergo Diels-Alder reactions only in those cases which carry a strongly electron-withdrawing N-substituent. Lewis acidity, solvent effect, lithium perchlorate in diethyl ether... 

An alternative synthesis of a thermally stable cyclopentadienyl functionalized polymer involved ring bromination of poly(oxy-2,6-diphenyl-l,4-phenylene), followed by lithiation with butyl lithium to produce an aryllithium polymer. Arylation of 2-norbornen-7-one with the metalated polymer yielded the corresponding 2-norbornen-7-ol derivative. Conversion of the 7-ol to 7-chloro followed by treatment with butyl lithium generated the benzyl anion which undergoes a retro Diels-Alder reaction with the evolution of ethylene to produce the desired aryl cyclopentadiene polymer, 6. 

Grieco investigated the intramolecular Diels-Alder reaction of imi-nium ions in polar media such as 5.0 M lithium perchlorate-diethyl ether and in water129 to form carbocyclic arrays. They showed that water as the solvent provided good-to-excellent yields of tricyclic amines with excellent stereocontrol (Eq. 12.58). 

A warning was given that the 5 molar solution in ether used as a solvent for Diels-Alder reactions would lead to explosions [1], Such a reaction of dimethyl acetylenedicarboxylate and cyclooctatetraene in this solvent exploded very violently on heating. The cyclooctatetraene was blamed, with no supporting evidence [2], It would appear desirable to find the detonability limits of the mixture with ether before any attempt is made to scale up. A safe alternative to lithium perchlorate/ether as a solvent for Diels-Alder reactions is proposed [3],... 

A) in Scheme l).9 Furthermore, asymmetric Diels-Alder reactions have been developed in LPDE solutions or using hetero-bimetallic catalysts containing lithium ions (compound... 

In 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

In the highly competitive arena surrounding the Pfizer compounds CP-263,114 and CP-225,917 (Figure 4.2), Nicolaou and co-workers employed a hydrozirconation—iodination sequence to produce vinyl iodide 4 [17]. Lithium—halogen exchange and subsequent conversion to enone 5 sets the stage for a Lewis acid assisted intramolecular Diels—Alder reaction affording polycyclic 6 as the major diastereomer (Scheme 4.3). 

If the alkenes and acetylenes that are subjected to the reaction mediated by 1 have a leaving group at an appropriate position, as already described in Eq. 9.16, the resulting titanacycles undergo an elimination (path A) as shown in Eq. 9.58 [36], As the resulting vinyltitaniums can be trapped by electrophiles such as aldehydes, this reaction can be viewed as an alternative to stoichiometric metallo-ene reactions via allylic lithium, magnesium, or zinc complexes (path B). Preparations of optically active N-heterocycles [103], which enabled the synthesis of (—)-a-kainic acid (Eq. 9.59) [104,105], of cross-conjugated trienes useful for the diene-transmissive Diels—Alder reaction [106], and of exocyclic bis(allene)s and cyclobutene derivatives [107] have all been reported based on this method. 

Despite the fact that Diels and Alder carried out a cycloaddition in water [2], it was not until 1980 that it was reported that large accelerations in the rates of the Diels-Alder reaction could be achieved in water [3], In addition, selectivity towards the endo product was also increased [4], For example, a 700-fold acceleration in the rate of reaction between cyclopentadiene and 3-buten-2-one (Scheme 7.3) was found in water as compared to reaction in 2,2,4-trimethylpentane. The addition of lithium chloride as a salting-out reagent... 

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