Nucleophilic DABCO

The reaction starts with the (relatively nucleophilic) DABCO undergoing conjugate addition to ethyl acrylate. This will form an enolate that can then attack the acetaldehyde in an aldol reaction. 

Together with a shift of the proton from the a-carbon to the alkoxide oxygen, the tertiary amine is eliminated from the addition product to yield the unsaturated product 3. Early examples of the Baylis-Hillman reaction posed the problem of low conversions and slow reaction kinetics, which could not be improved with the use of simple tertiary amines. The search for catalytically active substances led to more properly adjusted, often highly specific compounds, with shorter reaction times." Suitable catalysts are, for example, the nucleophilic, sterically less hindered bases diazabicyclo[2.2.2]octane (DABCO) 6, quinuclidin-3-one 7 and quinuclidin-3-ol (3-QDL) 8. The latter compound can stabilize the zwitterionic intermediate through hydrogen bonding. ... 

The nucleophilic displacement reactions with azide, primary amines, thiols and carboxylatc salts arc reported to be highly efficient giving high (>95%) yields of the displacement product (Table 9.25). The latter two reactions are carried out in the presence of a base (DBU, DABCO). Radical-induced reduction with tin hydrides is quantitative. The displacement reaction with phenolates,61j phosphines,6M and potassium phthalimide608 gives elimination of HBr as a side reaction. 

Catalysis by DABCO in the reactions of FDNB with piperidine, r-butylamine, aniline, p-anisidine and m-anisidine (usually interpreted as base catalysis as in Section B) was also assumed to occur by the formation of a complex between DABCO and the substrate14913. The high (negative) p-value of —4.88 was deemed inappropriate for the usually accepted mechanism of the base-catalysed step (reaction 1). For the reactions with p-chloroaniline, m- and p-anisidines and toluidines in benzene in the presence of DABCO a p-value of —2.86 was found for the observed catalysis by DABCO (fc3DABC0). The results were taken to imply that the transition state of the step catalysed by DABCO and that of the step catalysed by the nucleophile have similar requirements, and in both the nucleophilic (or basicity) power of the nucleophile is involved. This conclusion is in disagreement with the usual interpretation of the base-catalysed step. 

Oxidation of a sulfide to sulfoxide is known to be an electrophilic reaction, in contrast with nucleophilic oxidation of sulfoxide to sulfone. Since 2-nitrobenzenesulhnyl ehloride/K02 oxidizes sulfides to sulfoxides selectively, intermediate 48 must be the actual active intermediate. Moreover, in the presence of l,4-diazabicyclo[2.2.2.]octane (DABCO), which is a radical capturing reagent, the oxidation of methyl phenyl sulfide to the sulfoxide was inhibited. In order to further detect the intermediate 48, pure 5,5-dimethyl-1-pyrroline-l-oxide (DMPO) was used as a trapping reagent and spin adduct was obtained223. The ESR spectrum of the DMPO spin adduct was obtained by the reaction of 02 with 2-nitrobenzenesulfinyl chloride (hyperfine coupling constants, aH = 10.0 G and aN = 12.8 G). 

Substituted allyl alcohols can be prepared on insoluble supports under mild conditions using the Baylis-Hillman reaction (Figure 7.2). In this reaction, an acrylate is treated with a nucleophilic tertiary amine (typically DABCO) or a phosphine in the presence of an aldehyde. Reversible Michael addition of the amine to the acrylate leads to an ester enolate, which then reacts with the aldehyde. The resulting allyl alcohols are valuable intermediates for the preparation of substituted carboxylic acids [43,44],... 

Other activating nitrogen nucleophiles may be suitable too and DMAP and DBU are superior to DABCO in some cases ... 

When A-tosylaziridines were reacted with amines or thiols in acetonitrile in the presence of 5 mol% DABCO,50 the nucleophile attacked regiospecifically at the least substituted carbon of the aziridine ring. When a benzyl carbon was present in the aziridine ring, both possible products were obtained although the major product was from attack at the benzyl carbon. The catalytic role of DABCO (which may form an ammonium zwitterion which can deprotonate the nucleophile) is under investigation. 

The rate and the conversion of the Baylis-Hillman-reaction was significantly improved when nucleophilic non-hindered bases, such as diaza[2.2.2]bicyclooctane (DABCO, 6), rather than simple tertiary amines were used. Further improvements were observed when 3-quinuclidinole (3-QDL, 7) was employed, due to stabilization of the zwitterionic intermediate 2 by formation of intramolecular hydrogen bonds [14a-c]. Similar effects were observed by the addition of methanol [14d] or acetic acid [14e] to the reaction mixture (formation of intermolecular hydrogen bonds) or by the presence of a hydroxy group in the acrylate [14f ]. The rate of the reaction was decreased by the presence of substituents in the a-position of tertiary amines. This was explained by the decrease of the rate of the addition of the catalyst onto the acrylate [15]. 

Historically, the most effective N-based organic catalysts were nucleophilic unhindered tertiary amines such as DABCO (diazabicyclo[2.2.2]octane, 1) [23], qui-nuclidine (2), 3-hydroxy quinuclidine (3-HDQ, 3), 3-quinuclidone (4) and indoli-zine (5) (Fig. 5.1) [24]. A direct correlation has been found between pKa and the activity of the quinuclidine-based catalysts the higher the pKa, the faster the rate [25]. More recently, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 6), considered as a hindered and non-nucleophilic base, was shown to be a better catalyst than DABCO, or 3-HDQ [26]. The reason for the increased reactivity for this catalyst was attributed to stabilization of the zwitterionic enolate by delocalization of the positive charge. Other N-based catalysts such as N,N-(dimethylamino)pyridine... 

Much more important in determining pJCjH is how electron-rich the nitrogen is, and this is the cause of the glaring discrepancy between the basicity of quinuclidine and that of DABCO, or between the basicities of piperidine (p H 11-2) and morpholine (p-K"aH 9.8) or piperazine (pfCan 8.4). The extra heteroatom, through an inductive effect, withdraws electron density from the nitrogen atom, making it less nucleophilic and less basic. In this... 

A disadvantage of the Baylis-Hillman reaction is Its rate typically, several days reaction time are required. Pressure helps speed the reaction up, but as a catalyst DABCO is about the best. It is nucleophilic, because of the tied back alkyl groups, but importantly it is a good leaving group because it has a... 

Benzyl phosphates are less readily attacked by nucleophiles than methyl phosphates and they are more stable towards acidolysis than rm-butyl phosphates Benzyl phosphates are often used in complex polyfunctional targets because they are easily removed by hydrogenolysis. An indication of the reduced reactivity of benzyl phosphates is given in Scheme 7.17.32 Reaction of the phospho-nate diester 17.1 with one equivalent of 1 4-diazabicyclo[2 2 2]octane (DABCO) in refluxing toluene afforded the mono-deprotected derivative 17.2 in quantitative yield. Quinuclidine can also be used as the nucleophile. Assisted cleavage of benzyl phosphates is exemplified by the deprotection of the Shikimic Acid derivative in Scheme 7.18 using bromotrimethylsilane.33 34... 

The stability of carbocations flanked by n-coordinated organic moieties is dramatically enhanced so that they react easily with nucleophiles [125]. Magnus et al. [126] applied this principle to the synthesis of the core structure (208) of the diynene antibiotics esperamicim and calicheamicins. As shown in Scheme 68, diynene 205 was converted to enol silyl ether which was treated with Co2(CO)g to give dicobalt hexacarbonyl adduct 206. Exposure of 206 to 3 equiv of TiCU and 1 equiv of DABCO at —43 to —35 °C gave macrocycle 207 in 50% yield. 

The reaction of cyanomethyllithium with 2,4,6-tri-t-butylphenyl-dichlorophosphine enables a one-step preparation of the functionalised phospha-alkene (144). A new route to phospha-alkenes is provided by nucleophilic attack at the vinylic CH2 of the halogenophosphine (145), with displacement of halogen from phosphorus. Thus, with DABCO as nucleophile, the novel system (146) is formed.Treatment of the phosphino-substituted ylides (147) with Lewis acids results in the 2-phosphonio-l-phospha-alkenes (148), reported to be sufficiently stable for X-ray analysis, but also undergoing various addition reactions. 

---