DABCO asymmetric reactions

In an important achievement Vo-Thanh and co-workers realized that chiral ionic liquids such as 35 can act as chiral inducers for the asymmetric MBH reaction.The V-octyl-V-methylephedrinium trifluoromethanesulfonate salt 35, used as solvent in the DABCO-mediated reaction of methyl acrylate and benzaldehyde, produced the corresponding allylic alcohol in 60% yield and 44% ee after 7 days at 30 °C. 

Enolates, generated by Michael addition reactions of a,p-unsaturated esters or ketones, can add to aldehydes. If the Michael addition is carried out with a tertiary amine (or phosphine) then this is referred to as the Baylis-Hillman reaction. Typically, an amine such as l,4-diazabicyclo[2.2.2]octane (DABCO) is used. After the aldol reaction, the tertiary amine is eliminated and it can therefore be used as a catalyst (1.61). The reaction is somewhat slow (requiring several days), but rates may be enhanced with other amines such as quinuclidine or quinidine derivatives, the latter effecting asymmetric reaction with high levels of selectivity. ... 

Following on from the pioneering strategy of applying chiral solvents in asymmetric synthesis, developed by Seebaeh and Oei, chiral ILs have also been applied in the enantioseleetive MBH reaction. Vo-Thanh et al. first reported the asymmetrie induetion eaused by a chiral IL 309 as the only source of chirality in an asymmetric reaction. In the DABCO-catalyzed MBH reactions of aldehydes and methyl acrylate, they obtained enantioselectivities up to 44% ee by using an IL 309 with chiral cations derived from (-)-A-methyl-ephedrine as reaction media (Scheme 1.122). Importantly, the presence of the hydroxyl function on chiral ILs 309 is propitious for the transfer of chirality. 

Thiourea catalyst 139 was also screened in the asymmetric Friedel-Crafts reaction between 2-naphthol trans-nitrostyrene (73% yield 0% ee 18 h in toluene at -20 °C and 10 mol%) [277], in the asymmetric aza-Michael reaction of O-benzyl-hydroxylamine to chalcone (72% conv. 19% ee 72 h in toluene at 20 °C and 20mol% catalyst loading) [293], and in the asymmetric Morita-BayUs-HiUman [176, 177] reaction between cyclohexenecarbaldehyde and 2-cyclohexene-l-one (20% yield 31% ee 46 h at rt and 20mol% DABCO and 139) [310]. In aU these transformations, thiourea 139 proved to be not competitive to the organocatalysts probed for these transformations under identical screening conditions and thus was not employed in the optimized protocols. 

The catalyst screening experiments were performed in the asymmetric Henry addition of nitromethane (10 equiv.) to 4-nitrobenzaldehyde in the presence of DABCO (20mol %) as the base and (thio)ureas 157, 158, 163, and 170-175 (each 10mol% loading). After 12h in reaction time at room temperature and in THF as the solvent, the corresponding Henry adduct was obtained in excellent yields (99%) but with very low ee values (7-17%) nearly independently of the sterical hindrance of the axiaUy chiral backbone skeleton (e.g., 172 and 174 each 99% yield 11% ee). Thioureas appeared slightly more enantioselective (e.g., 163 83% yield, 33% ee 171 99% yield, 15% ee) than their urea counterparts probably due... 

Scheme 6.163 Product range of the asymmetric MBH reaction catalyzed by bisthiourea 176 in the presence of DABCO.

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

This coupling of an activated alkene derivative with an aldehyde is catalyzed by a tertiary amine (for example DABCO = 1,4-Diazabicyclo[2.2.2]octane). Phosphines can also be used in this reaction, and enantioselective reactions may be carried out if the amine or phosphine catalyst is asymmetric. 

During the course of the Baylis-Hillman-reaction two stereocenters are formed, one of which remains in the Baylis-Hillman-product. An obvious concept for the development of an asymmetric version of the reaction represents the use of an enantiomerically pure acrylic acid derivative. The use of enantiomerically pure menthyl acrylates resulted, but only in certain cases, to respectable diastereomeric excesses [21]. A significant improvement was reported in 1997 by Leahy and coworkers who used the Oppolzer-sultame as a chiral auxiliary in DABCO-catalyzed Baylis-Hillman-reactions (Scheme 2) [22]. In this reaction, the... 

Asymmetric Baylis-Hillman reactions using sugar acrylates have been reported to proceed with moderate diastereoselectivity (5-40% ee) [23]. The reaction of camphor-based chiral acryloylhydrazides with aldehydes in the presence of DABCO afforded /1-hydroxy-a-methylene carbonyl derivatives in 68-92% yield with high diastereoselectivity (up to 98% de) [24]. Both diastereomers could be selectively obtained simply by changing the solvent. 

The first chiral catalysts were developed from achiral molecules such as DABCO, quinuclidine, indolizine or pyrrolizine-derived catalysts by introducing asymmetric functions. Hirama and co-workers examined chiral C2-symmetric 2,3-disubstituted l,4-diazabicyclo[2.2.2]octanes such as 2,3-(dibenzoxymethyl)-DABCO (29) as catalysts for asymmetric MBH reaction between 4-nitro-benzaldehyde 27 and methyl vinyl ketone (MVK, 28) (Scheme 5.6) [57]. The additive function of the catalyst compared to the achiral DABCO resulted, however, in diminished reactivity, and the reaction required high pressure in order to... 

Scheme 5.6 Asymmetric MBH reaction using chiral DABCO 29.

The Baylis-Hillman reaction has become a very powerful carbon-carbon bond forming reaction in the past 20 years. A typical reaction involves an activated olefin (i.e., an acrylate) and an aldehyde in the presence of a tertiary amine such as diazobicyclo-[2.2.2]octane (DABCO) to form an a-meihylhydroxyacrylale. A host of activated olefins have been utilized including acrylates, acroleins, a, 3-unsaturated ketones, vinylsulfones, vinylphosphonates, vinyl nitriles, etc. The Baylis-Hillman has been successfully applied inter- and intramolecularly. In addition, there are numerous examples of asymmetric Baylis-Hilhnan reactions. Reviews (a) Ciganek, E. Org. React. 1997, 51, 201-478. (b) Basavaiah, D. Rao, P. D. Hyma, R. S. Tetrahedron 1996, 52, 8001-8062. (c) Fort, Y. Berthe, M. C. Caubere, P. Tetrahedron 1992, 48, 6371-6384. 

The Morita-Baylis-Hillman (MBH) reaction is an important 100% atom economic transformation that allows the formation in one step of a flexible allylic alcohol motif. Efforts in this field have been directed recently to the solution of two problems to enhance the generally sluggish reaction rate and to achieve asymmetric catalytic versions. Scheme 1.15 gives the catalytic cycle of the MBH reaction. The catalyst is a highly nucleophilic tertiary amine, generally DABCO, or a tertiary phosphine, which adds to the oc,P-unsaturated electrophile in a 1,4 fashion to deliver an enolate that, in turn, adds to the aldehyde. A critical step is the proton transfer from the enolizable position to the oxygen atom this process is catalysed by an alcohol that plays the role of a proton shuttle between the two positions. Water has also been reported to strongly speed up the reaction at a well-defined concentration. Moreover, the... 

A remarkable increase in enantioselectivity achieved by applying high pressure was observed by Hirama et al. [81] for an asymmetric Baylis-Hillman reaction, in addition an enhancement of the reaction rate was also found. The Baylis-Hillman reaction refers to the condensation of acrylates and aldehydes catalyzed by tertiary amines. Using various enantiopure 2,3-disubstituted l,4-diazabicyclo[2.2.2]octanes (DABCOs) as chiral amine bases the influence of high pressure on the reaction... 

Chiral 2,3-disubstituted DABCOs promote asymmetric Baylis-Hillman reactions under high pressure. While the yields are acceptable, the enantioselectivity is dismal. 

In pyridine solutions, the statistically corrected relative catalytic coefficients of tertiary amines for 1-methylindene isomerization decreased in the order24 4. quinuclidine, 80 DABCO, 10 triethylamine, 1. The smaller catalytic effectiveness of DABCO than quinuclidine is attributable to its weaker basicity is —30eu for each of these bicyclic bases. On the other hand, triethylamine is about as basic as quinuclidine, but must lose considerable rotational freedom in the rate-limiting proton transfer. This is reflected in the more negative entropy of activation (—39eu) for the triethyl-amine-catalyzed reaction. In pyridine solution, there is a close correlation between pa s of the catalyzing base and A// for 1-methylindene isomerization. Asymmetric catalysis was demonstrated in the quinine-catalyzed isomerization of optically active 1-methylindene in pyridine at 25°C the dextrorotatory indene isomerized nearly twice as fast as its enantiometer247. 

Imamoto reported that Pd-catalyzed coupling of phosphine-borane with aryl halides is useful for preparation of asymmetric phosphines. Phosphines can be easily isolated from phosphine-boranes by exchange reaction with amines such as pyrrolidine and DABCO [10]. Lipshutz found that aryl nonaflates ( Nf = nonafluorobutanesulfonate) and triflates are good substrates for coupling with BHs-stabilized diaryIphosphines. Selective coupling with nonaflate without... 

In 2011, Palomo [114] reported the first enamine-mediated direct asymmetric a-alkylation of aldehydes with electron-deficient allylic halides, in which the key C—C bond-formation proceeds via an 8 2 pathway. The reaction is efficiently catalyzed by co-catalysts system diphenylprolinol derivative/DMAP or DABCO... 

A phosphine sulfonamide derived from L-threonine promotes aza-Morita-Baylis-Hillman (aza-MBH) reactions of sulfinylimines in up to 96% yield and 97% ee. A review describes the synthesis of chiral amines under mild conditions via catalytic asymmetric aza-MBH reactions. Proline/DABCO (l,4-diazabicyclo[2.2.2]octane) co-catalysis of enantioselective aza-MBH reactions gives good to high yields and up to 99%... 

In the catalytic asymmetric aza-Morita-Baylis-HiUman reaction using unactivated methyl acrylate, the combined use of a La(0- Pr)3/(5, 5 )-TMS-linked-BINOL complex with a catalytic amount of l,4-diazabicyclo[2.2.2]octane (DABCO) promoted the aza-Morita-Baylis-Hillman reaction of a broad range of A-diphenylphosphinoyl imines." ... 

---