Pyrrolidine Michael-type additions

Pyrrolidine Amines and Pyrrolidine Amine Salts as Catalysts for Michael-Type Addition of Ketones to Activated Olefins... 

Scheme 2.38 Chiral pyrrolidine-derived catalysts for Michael-type addition of ketones to activated olefins.

It is noteworthy that chiral organic bases such as pyrrolidines and cinchonines or cinchonidines were recently grafted onto a MCM-41 support.1183,1841 These materials catalyse enantioselective Michael-type addition between ethyl 2-oxocy-clopentanecarboxylate and methyl vinyl ketone[183] as well as thiol and 5-methoxy-2(5Z/)-furanone.[184] Although ee was only modest (maximum ee 35 %), these attempts are very promising. 

Like most other aspects of the luzopeptin effort, deblocking of hard-won dipeptides 106 and 107 turned out to be a delicate proposition. In derivatives of proline and pipecolinic acid, the serine segment had been extricated from its protective webbing by A-deacetylation with pyrrolidine in aeetonitrile and Kunieda cleavage of the oxazolone. However, reaction of 106 with pyrrolidine furnished 109 (30%) as the sole identifiable compound. Evidently, pyrrolidine was basic enough to promote p-elimination of acetate and subsequent Michael-type addition to intermediate 108, a significant fraction of which may have been lost to polymerization. Other amines, such as ethylamine, diethylamine. 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

The net effect of the Stork enamine sequence is the Michael addition of a ketone to an a, -unsaturated carbonyl compound. For example, cyclohexanone reacts with the cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael-type adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone product (Figure 23.8). 

The mechanism of the formation of lff-pyrrole-2,3-diones 494 involves first the Michael-type attack of nitrogen atom of NH2 group of the urea derivative on C(5) in the furandione ring. Later, the molecule of water was eliminated and compound 494 was obtained. Nucleophilic addition of 1,2-DABs 155 to pyrrole-2,3-dione 494 lead to quinoxalin-2-ones 495. These compounds arise fi om the sequential attacks of 1,2-DABs at the C(3) and C(2) atoms of pyrrolidine, respectively, followed by the elimination of water and pyrrole ring opening, and the basic hydrolysis of this intermediate provides the final product 495. A possible reaction scenario is outlined in Scheme 2.111. 

The use of hydrazone or enamine derivatives of ketones or aldehydes offers the advantage of stcreocontrol via chelated azaenolates. Extremely useful synthetic methodology, with consistently high anti selectivity, has been developed using azaenolates based on (S)- or (R)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP or RAMP)51 58 (Enders method, see Section 1.5.2.4.2.2.3.). An example which illustrates the efficiency of this type of Michael addition is the addition of the lithium azaenolate of (5 )-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of propanal (R = II) to methyl (E )-2-butenoate to give the nub-isomer (an 1 adduct) in 80% yield with a diastereomeric ratio > 98 2,... 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

A stereoselective synthesis of substituted pyrrolidines has been achieved by a sequential domino Michael addition and intramolecular carbozincation. The intermediate zinc-copper reagent obtained after cyclization can be trapped with an electrophile such as allyl bromide (Scheme 18).180 Addition of zincated hydrazones 52 on alkenyl boronates, followed by a trapping with an electrophile, provides adduct of type 53 with good yield and high diastereoselectivity (Scheme 19).181 By this addition/trapping sequence, several contiguous stereogenic centers are created in one step. 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

In addition, several supported chiral ionic liquids have been investigated for these reactions. Therefore, Wang et al. have developed a new type of polymer-immobilised pyrrolidine-based chiral ionic liquids, which were capable of inducing the Michael addition of ketones to nitrostyrenes in high yields. 

Another reaction type involving iminium salts led to pyrrolidines via the trapping of azomethine ylides generated from sarcosine and aqueous formaldehyde (Lubineau et al, 1995). The efficiency of [3+2] cycloaddition was related to the water content. Indeed, adding THF to the reaction medium decreased the rate of the Michael addition, which competed with the desired pyrrolidine synthesis ... 

Independently, Alexakis and coworkers reported that 2,2 -bipyrrolidine catalyst 28 showed excellent catalytic activity in several types of asymmetric Michael addition reactions [143], It has been postulated that the isopropyl group on one of the Cj-symmetric pyrrolidine rings should block not only the back face against the approach of Michael acceptors but also shift the equiUbrium towards one of the two rotamers. Since then, closely related catalysts have also been reported [144]. Furthermore, different types of catalysts such as 29 have been shown to be useful in asymmetric Michael addition reactions [145-148],... 

In parallel, Xu and coworkers discovered that in the presence of similar I L-tagged pyrrolidines 84c,d the reaction proceeded nearly as efficiently in the [bmimJIPFs] medium, so there is no need to dehver the acid co-catalyst (TFA) to the system because this role is obviously played by the IL fragment [96]. Catalysts 84a,b were recovered from the reactant medium by precipitation with ether, while the 84c,d/ IL systems were reused after product extraction without further purification. Four reaction cycles of catalysts 84 did not reduce reaction diastereo- and enantioselec-tivities however, the recovered catalysts gradually became less active with each cycle. Surfactant-type IL-supported asymmetric organocatalyst 84e synthesized by Luo and Cheng and coworkers in 2006 catalyzed Michael addition to nitroalkenes with high stereoselectivities in water without any additives [97]. 

Reversing the position of the aldol electrophile, Enders and coworkers developed a type ce approach to complex 3-pyrrolin-2-ones that involved a quadruple cascade process (Scheme 91 2014S1539). Treatment of cinnamaldehyde (353) and the a-ketoamide 354 with pyrrolidine catalyst 355 and NaOAc gives the fused 3-pyrrolin-2-one 357. The mechanism of the reaction includes a Michael addition by the amide followed by aldol condensation to generate the 3-pyrrolin-2-one intermediate 356 subsequent Michael and aldol transformations with a second equivalent of 353 then gives the fused cyclopentene ring. 

Asymmetric Michael addition reaction represents one of the most extensively explored organoctalytic transformations. Chiral secondary amines such as pyrrolidines have been proved to very effective catalysts for the reactions of Michael donors such as cyclohexanone and aldehydes [31]. Ala-Ala dipeptide 57 [32] was firstly found to be viable catalyst for the reaction of cyclohexanone and nitrosty-rene. Later, some primary amine-amide type catalysts such as 55 [33a], 56 [33b-c] and 58 [33d] have also been indentilied for the same reactions (Scheme 5.16) with slightly lower activity compared with typical chiral pyrrolidine catalysis. 

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