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Science Vision 16 (3) July-September Research Review ISSN (print) 0975-6175 ISSN (online) 2229-6026

Organocatalysts: A powerful tool for asymmetric Michael addition

K. Vanlaldinpuia1* and P. B. Lalthanpuii2

1Department of Chemistry, Pachhunga University College, Aizawl 796001, India 2Department of Zoology, Pachhunga University College, Aizawl 796001, India

Received 18 August 2016 | Revised 24 August 2016 | Accepted 29 August 2016

ABSTRACT

In recent years, asymmetric has emerged as powerful tools for the synthesis of a variety of chiral molecules. Ready availability of the catalysts, low toxicity, simple operational pro- cedures and mild reaction conditions associated with organocatalysis makes it an attractive method to synthesise diverse complex structures. Here, a short review on the development and applications of chiral organocatalysts for asymmetric Michael addition reactions has been de- scribed.

Key words: Asymmetric reaction; organocatalysis; Michael addition.

INTRODUCTION

Z Michael reaction or Michael addition or con- X Z EWG + EWG jugate addition is one of the most important methods for the mild formation of C-C bonds.1 Y X Y It may be defined as the of X, Y, Z = R oZr EWG stabilized anions (e.g. , ,X etc.) Z EWG + EWG EWG = COR, ZCO2R. CN, NO2, etc to an α, β-unsaturated carbonyl and relatedX com- Z EWG pounds.2 It was named after an American Ychem-+ EWG X Y ist Arthur Michael (1853-1942) who reportedY the X, Y, Z = R or EWG X Y reaction that bears his name in 1887.2,3 XE,W YG, Z= =CORR o,r CEOW2RG. CN, NO2, etc

EWG = COR, CO2R. CN, NO2, etc

Corresponding author: Vanlaldinpuia Scheme 1. Michael addition. Phone: : +91-9862086476 E-mail: [email protected]

CC BY-SA 4.0 International 2016 123 Organocatalysts: A powerful tool for asymmetric Michael addition

The work done by Arthur Michael in 1887, their claim was without merit. on the formation of a cyclopropane derivative by the reaction of diethyl 2,3-dibrompropionate with diethyl sodiomalonate (Scheme 2), was motivated by the work of Conrad and Guthzeit.4

Br

COOEt + EtOOC COOEt COOEt + EtOOC COOEt Br Na Br Na

1 2 3 2

Conrad & Guthzeit 1884 E t O O C C O O E t Michael 1887 COOEt

Br 4

EtOOC COOEt COOEt

5

Scheme 2. Experiments done by Conrad & Guthzeit in EtOOC COOEt 1884 and Michael in 1887. EtONa / EtOH CO Et + EtOOC COOEt Ph 2 COOEt When Michael treated 2-bromacrylic acid rt, 4 days Ph ester with sodiomalonic acid ester, he obtained EtOOC COOEt EtONa / EtOH the same product reported by ConradCO Et + & E Guth-tOOC COO Et 4 Ph 2 COOEt zeit and realized that this reaction could only rt, 4 days Ph work by assuming an addition reaction to the double bond of the acrylic acid.2b,3 He then con- Scheme 3. First example of Michael addition reaction firmed this postulation by reacting diethyl malo- in 1887. nate and ethyl ester of cinnamic acid obtaining the very first Michael adduct (Scheme 3).2 Soon The Michael addition benefits from mild re- after its publication, Claisen5 claimed priority of action conditions, high functional group toler- the discovery of the reaction. Claisen and Kom- ance, a large host of polymerizable monomers nenos6 both observed addition products to dou- and functional precursors as well as high conver- ble bonds as side-products earlier in 1883 while sions and favourable reaction rates.9a These fea- investigating condensation reactions of malonic tures make the Michael addition reaction an im- acid with . However, after the Claisen- portant organic transformation and the resultant Komenos report, condensation-addition prod- compounds have been used in the synthesis of ucts like theirs were also shown to formed in the several natural products, and drug molecules, reaction of formaldehyde with numerous emerging technologies including bio- by Perkin Jr.7 and in the reaction of benzalde- medical applications such as gene transfection, hyde with ethyl acetoacetate by Hantzsch.8 cell scaffolds, and tissue replace- Hence, according to biographer Tokoroyama,3 ments.10a,10b,10c,9b,11,12

124 Vanlaldinpuia and Lalthanpuii

ORGANOCATALYSIS 93% ee. O O The term “organocatalysis” was given by 13 Ahrendt et al. to sum up a group of organic MeCN, 11 (3 - 47 mol%) N COOH compounds used as catalysts to promote various O H O 0 asymmetric transformations. It is a branch of O r.t. - 80 C 10 in which a reaction is mediated solely 9 11 by small organic molecules in sub-stoichiometric Yield = 99 % quantities.14 Before 1960, there wereO few exam- O ee = 93 % ples of asymmetric organocatalysis but all of MeCN, 11 (3 - 47 mol%) them gave low (less than 20 N COOH H 15 0 O %) and hence, have no syntheticO O values. But inr.t . - 80 C 16a,b 1960, Pracejus et. al. reported that the use of 10 9 11 cinchona alkaloid derivative (8) catalysed the Yield = 99 % addition of methanol to phenylmethylketene (6), ee = 93 % giving (-)-α-phenyl methylpropionate (7) with 74 % enantiomeric excess (ee). Scheme 5. L- catalysed asymmetric Robinson annulations.

O H O Despite theseO wonderfulN results, there was not much improvement in the field of organo- O O MeOH, 3 (1 %) catalysisO for almost thirty years. But, since the year 2000, there was an explosive growth in this o Toluene, -110 C field and the use N of chiral primary and secon- dary amines, chiral aziridinium and oxaziridin- 6 7 ium salts, cinchona8 alkaloids, etc. as a catalysts Yield = 93 % became a powerful tool in asymmetric synthe- ee = 74 % sis.14d Recently, asymmetric catalysis has been classified into three fields in which organocataly- sis has been placed in between metal catalysis H and enzymatic transformation.18 O O N O O O MeOH, 3 (1 %) O ASYMMETRIC MICHAEL ADDITION USING ORGANOCATALYSTS o Toluene, -110 C N Asymmetric organocatalytic Michael addi- 6 7 8 tion has attracted a great deal of interest in re- Yield = 93 % cent years due to its environmental friendliness ee = 74 % Scheme 4. Cinchona alkaloid catalysed asymmetric and the generation of multiple stereogenic cen- addition of methanol. tres in a single step. Since the pioneering works of List19 and Barbas,20 organocatalytic asymmet- Subsequently in 1970s, Hajos et. al.17 also ric Michael additions have been thoroughly in- 21 reported for the first time, the use of amino acid vestigated, and in doing so, some well- L-Proline 11 as a catalyst for highly enantioselec- designed thiourea organocatalysts, such as pri- tive Robinson annulations reaction giving up to mary and tertiary amine-thiourea based cata-

125 Organocatalysts: A powerful tool for asymmetric Michael addition

Table 1. Comparison between three classes of asymmetric catalysis. Metal based catalysts Organocatalysts Enzymes Transition metal A particular carbon heteroatom Combination of hundreds of amino as the active centre. skeleton that gives individual acids; however, only some of them characteristics to the active site. are active in the catalytic sites. Expensive and moisture /oxygen Not harmful in small amounts and No toxicity at all. sensitive and give some problem in often allow mild reaction the purification process, as only conditions and simple working small amounts of metals procedures. contaminants is tolerated for pharmaceuticals products. The catalysts loadings are often The catalysts loadings are typically The catalysts loadings are low. very low (up to 1000000/1 in under 100/1 in Substrate/Catalyst. Substrate /Catalyst). Both the enantiomer can be Both the enantiomer can be Synthesis of both the enantiomers obtained. obtained. is difficult.

lysts, proline and its derivatives, and many other to electrophilically activate the enone via hydro- amine based organocatalysts have been success- 19-22a gen-bond donation to the carbonyl oxygen. fully developed for this reaction. Other O O classes of catalysts most frequently used in O 12 (5 mol%), 4oC Ph asymmetric Michael additions are cinchona al- R2 12 = R1 + H R N OMe kaloids and their derivatives.23 In this review, H Catechol 2 H O R Ph different types of Michael addition reaction us- 1 ing different organocatalysts will be highlighted. O O O 12 (5 mol%), 4oC Ph Yield = Upto 87% R2 12 = ee = Upto 99% R1 + H R N OMe MICHAEL ADDITIONH OF C-NUCLEOPHILESCate chol 2 H O R Ph 1 Most of the organocatalysts catalysed Mi- Yield = Upto 87% chael addition of C- proceeds via ee = Upto 99% or iminium ion intermediate. Many successes have been realised by applying organo- Scheme 6. Diphenylprolinol methyl ether-catalysed catalysts such as proline derivatives to highly Michael additions of aldehydes to simple enones. reactive Michael donors or acceptors, but Mi- chael additions of simple aldehydes to simple In the same year, Peelan et al.26 also reported enones have received little attention.24 In 2005, MacMillan imidazolidinone catalyst (13) cata- Chi and Gelmann25 reported that diphenylproli- lysed intermolecular -enone Michael nol methyl ether (12) could catalysed intermo- addition reaction using catechol as an additive lecular Michael addition of simple aldehydes to (Scheme 7). relatively non-activated enones with enantiose- O O O lectivities up to 99% with catalyst loading of 1-5 O 13 (20 mol%) R N mol% (Scheme 6). Although some of the reac- R + 2 13 = R H 1 H R2 tions proceeded smoothly with only the chiral Catechol, 20 mol% Bn N O R R pyrrolidine as a catalyst, others required the use 1 H of catechol as a co-catalyst, which was believed Yield = Upto 86% ee = Upto 92%

126 Vanlaldinpuia and Lalthanpuii

O O O Another important class of organocatalysts O 13 (20 mol%) N R2 13 = for intermolecular Michael addition of C- R1 + R H H R2 Bn nucleophiles is cinchona alkaloids and its deriva- O Catechol, 20 mol% N R R1 H tives. Some important reactions includes enanti- Yield = Upto 86% oselective addition of α-substituted β-keto or α- ee = Upto 92% cyano esters to α, β-unsaturated aldehydes,35 α- Scheme 7. Imidazolidinone-catalysed Michael addi- substituted β-keto esters to a wide range of vinyl 36 37 tions of aldehydes to simple enones. , cyanoacetates to , β-keto esters to acrolein and methyl vinyl ,38 and Michael additions of highly activated nucleo- to chalcones39. Some of the cata- philes such as malonates27 or nitroalkanes28 to lysts used for this transformation are shown in simple enones were also reported. Unactivated Figure 1. ketones or aldehydes have also been used with highly activated Michael acceptors such as nitro- Ar Ar Ar .29 Many other organocatalysts were syn- thesised and utilized for Michael addition of: OH Bn p-Tol N O nitroalkanes to enones, α, α-dicyano olefins to α, p-Tol β-unsaturated aldehydes, sulfonium ylides to α, β N Ar = 3,5-(Ph)2C6H3 p-Tol O -unsaturated aldehydes, nitroalkanes to unsatu- N Bn rated ketones and heteroatomic compound to α, OH p-Tol 30-34 β-unsaturated aldehydes. . 2BF4 Ar Ar Ar

Cl N Ph 18 19 OH Cl N Ph OH Ar Ar HAOr N OR Ph HO N Ph p-Tol R = OR OH O Bn N R = O N N O N p-Tol N H N N H N Ar = 3,5-(Ph)2C6H3 p-Tol N H O N H N Bn 14 O H 1 5 p-Tol C1l4 N P h 15 OH 2BF4 Cl N Ph Ar Ar A r OH HO Et N Ph3Si Ph N OR N Ph3Si H H Et N HO 18 H H 19 OR R P =h OR O N N CF3 N OR N N CF3 R = O H H N N MeO N S Figure 2. CH -symmetricH phase-transfer catalyst (18) N H N MeO 2 S N N H N H N H and TaDiAS (19) N H CF3 N CF3 N H N 14 1 6 1 5 17 Phase transfer catalysts were also utilized for 14 15 16 17 asymmetric Michael addition and the reactions

Ph3Si Et N are usually carried out in two- or three phase H H 24,40a,b,c Ph3Si Et N OR H H N N CF3 system. N-spiro C2-symmetric chiral qua- OR N N CF3 H H ternary ammonium bromide (18) synthesised by N MeO S N H H Maruoka and co-wokers, and a tartrate-derived MNeO H S CF diammonium salt (TaDiAS, 19) have been N H N 3 CF3 shown to be efficient in mediating phase-transfer 16 N 17 16 1 7 Michael additions. Figure 1. Some cinchona alkaloids derivatives used for Michael addition.

127 Organocatalysts: A powerful tool for asymmetric Michael addition

44 MICHAEL ADDITIONS OF C-NUCLEOPHILES to 80% ee (Scheme 9). In 2005, Hoashi et al. TO VINYL SULFONES AND α, β- extended enantioselective organocatalysed Mi- chael addition methodology to α, β-unsaturated UNSATURATED IMIDES imides by the use of a bifunctional thiourea as catalyst (Scheme 10). Bartoli et al.45 also showed The first highly enantioselective Michael ad- that cinchona alkaloids were highly efficient dition of α-alkyl- or α-aryl-α-cyanoacetates to catalysts for the Michael addition of 1,3- 41 vinyl sulfones was reported by Li et al. , em- dicarbonyl compounds to maleimides (Scheme ploying a cinchona alkaloid catalyst 20 (Scheme 11). 8). Liu et al.42 also reported bifunctional thiourea tertiary amine derivatives of simple chiral dia- Catalyst 22 1 mines (21) for similar reaction. R PhO S SO Ph (25 mol%) 2 2 OHC SO2Ph N N + H i-Pr OHC R2 o R1 R2 Catalyst 20 or 21 CHCl3, -60 C SO2Ph EtO C CN CO Et 3 2 (20 mol%) 2 22 2 R SO2R Upto 80% ee + R1  SO R2 R1 CN Toluene, -25 oC 2 o Catalyst 22 1 or -40 C R PhO S SO Ph (25 mUopl%to) 97% eOe HfoCr 20 SO Ph 2 2 Upto 96% ee for 21 2 N N 2 + H i-Pr OHC R CHCl , -60 oC R1 R2 Catalyst 20 or 21 3 SO2Ph OH EtO2CCaCtaNlyst 20 or 21 Ph S 22 CO2Et R3 SO R2 (20 mol%) EtO C CN 2 CO Et 3 2 (20 mol%) P2h Upto 80% ee + 2 OR R SO2R R1  SO R2 N NHAr R1 CN Tolue+ne, -25 oC 2 1  2 1 R = o R HSO2R R CN oN Toluene, -25 C SchemeNM 9.e 2iPBP-catalysed Michael additions of alde- or -40 C Upto 97% ee foor 20 or -40 C Uhydespto 9 to7% vinyl ee f osulfones.r 20 N H Upto 96% ee for 21 UpAtor =9 63%,5 -e(eC Ffo3r) 22C16H3 OH Ph S CF3 20 O 21 OH Ph SO (NC)2HC H O O Ph 23 10 mol% S OR N NHAr RPh N CatalyOstR 20 or 21 N NH+ A Cr H2(CN)2 R N R = EtO2C CN H o CO Et 3 2 (20 mol%) NMe H Toluene, 20 C F3C N N 2 RN SO2R R = 2 NMe H H + N R1  SO R2 2 NMe R1 NCN H Toluene, -25 oC 2 Upto 92% ee 2 N H o Ar = 3,5-(CF3)2C6H3 23 or -40 C Upto 97% ee for 20 Ar = 3,5-(CF3)2C6H3 20 21 CF3 O Upto 96% ee for 21 20 O ( N C ) 2 H C H 21O O 23 10 mol% S OH R N + CH (CN) Ph S R N 2 2 o Toluene, 20 C F3C N N Ph H H OR N NHAr NMe H Upto 92% ee 2 R = NMe 23 N 2 N H Scheme 10. Thiourea catalysed Michael additions of C Ar = 3,5-(CF ) C H 3 2 6 3 -nucleophiles to α, β-unsaturated imides. 20 21 O OMe O Scheme 8. Cinchona alkaloid- and thiourea-catalysed O O R3 24 (10-20 mol%) O Michael additions of cyanoacetates to vinyl sulfones. N Bn OH 1 3 + N Bn O  R R o  N 2 CH2Cl2, -60 C R 1 R2 O Mosse et al.43a,b employed N-i-Pr-2S,2'S-bi- O R N H pyrrolidine (iPBP) (22) for asymmetric conden- Upto 98% ee 24 sation of aldehydes onto vinyl sulfones giving up

128 Vanlaldinpuia and Lalthanpuii

amine organocatalysts were used by Chen and O OMe O co-workers to promote the enantioselective Mi- O O R3 24 (10-20 mol%) O N Bn OH chael addition of arylthiols to α, β-unsaturated 1 3 + N Bn O  47 R R o  N carbonyl compounds (Scheme 13). Three other 2 CH2Cl2, -60 C R 1 R2 O enantioselective conjugated additions of thiols to O R N H α, β-unsaturated aldehydes were also reported by Upto 98% ee 24 Marigo et al.,48 Rios et al.49 and Wang et al.50

Scheme 11. Cinchona alkaloid catalysed Michael addi- S O O tions of C-nucleophiles to α, β-unsaturated imides. N HN 26 10 mol% NH + ArSH o MICHAEL ADDITION OF N-, S- AND O- CH2Cl2, 0 C n n SAr F C NUCLEOPHILES 3 Yield = Upto 99% CF3 Asymmetric Michael addition of nitrogen- ee = Upto 85% 26 centred heterocyclic nucleophiles to electron

deficient olefins is of great importance in the S O O area of heterocyclic chemistry.24 But, there are N HN 26 10 mol% only few reports of the use of organocatalysts for NH + ArSH o 46 this reaction. In 2006,CH 2C Wangl2, 0 C et al. employed n n SAr F3C cinchona alkaloids 25 for enantioselective Mi- chael addition of N-heterocycles such as 1H- Yield = Upto 99% CF ee = Upto 85% 3 benzo[d][1,2,3]-triazole to nitro olefins giving 26 the products in moderate to high enantioselectiv- ities (Scheme 12). Scheme 11. Thiourea-catalysed Michael additionsH of arylthiols to enones.

TheN first organocatalysed asymmetricN synthe- N 25 10 mol% N HO + NO2 sis of chiral benzopyrans was reported by Gov- N R N 51 H -25 oC, CH Cl ender et al. (Scheme 14). The overallH reaction N 2 2 NO2 HO H chain afforded benzopyrans with aromatic C-2 substituentsR in up to 60% yield and 60% ee, H N Yiewhileld = U p theto 8 7 C%-2 aliphatic analogues could be ob- ee tained= Upto in94 up% to 90% ee, but with only25 low yields. N N 25 10 mol% N 1 NO N HO R1 CHO R CHO Ar N + 2 27 10 mol% R o N H + R2 N Ar -25 C, CH2Cl2 NO H N 2 HO CHO o 2 H OTMS H OH CH2Cl2, 20 C O R R  Yield = Upto 90% Ar = 3,5-(CF3)2C6H3 1 N R1 CHO Ar ee = Upto 90% Yield =R Upto 87%CHO 27 10 mol% 27 ee = Upto 94% + R2 25 N Ar CHO o 2 H OTMS OH CH2Cl2, 20 C O R Scheme 12. Cinchona alkaloid-Michael additions of N- heterocycle. Yield = Upto 90% Ar = 3,5-(CF3)2C6H3 ee = Upto 90% 27

Bifunctional chiral thiourea and tertiary Scheme 14. Oxa-Michael reactions catalysed by L- proline derivative.

129 Organocatalysts: A powerful tool for asymmetric Michael addition

NTRAMOLECULAR ICHAEL ADDITION COR1 2 I 1 M O R COR EtO2C CO2Et 29 20 mol% R2 N + t-Bu 52 o CHO Mangion and MacMillan reportedDiox a anne , in-20 C Bn N CHO N H tramolecular Michael additionH of a formyl-enal catalysed by L-proline in DMSO, which they Yield = Upto 98% 29 used it for the total syntheses of two biologically de = Upto 96% ee = Upto 97% active natural products, (-)-brasoside and (-)- 53 littoralisone. In the same year, Hayashi et al. Scheme 16. Intramolecular reductive Michael reac- have also employed a naphthylamide catalyst tions catalysed by imidazolidinium salt. derived from cysteine (28) for asymmetric in- tramolecular Michael reactions such as those implicating formyl enones, which led to the NITRO-MICHAEL ADDITIONS OF C- stereoselective formation of cis-disubstituted NUCLEOPHILES cyclopentane skeletons (Scheme 15). Enantioselective Michael addition of car- bonyl compounds to nitroalkenes has been of CHO O great interest dueS to its imperturbable approach R1 28 10 mol% R1 for the synthesis of synthetically useful γ-nitro N 2 2 o 55HN O R R CHO Acetone, 0 C O carbonyl compounds.H2 L-Proline was first used R2 forR2 intermolecularC F catalyticCOO conjugate addition of carbon nucleophile3 to nitroalkenes, but found Yield = Upto 100% 28 CHO to be ineffective as it afforded only poor enanti- O de = Upto 90% 56 1 S oselectivity. Since then, a large number of or- R1 28 10 mol% R ee = Upto 99% ganocatalysts have been designed and developed 2 2 o N HN O R R CHO Acetone, 0 C O H2 for this transformation and among them, pyr- R2 R2 CF COO rolidine-based catalytic systems was found to be 3 the most successful.22 A common feature of Yield = Upto 100% 28 de = Upto 90% these catalytic systems is a hydrogen-bond do- ee = Upto 99% nor at the α-position of the pyr- rolidine nitrogen atom, which is believed to play Scheme 15. Intramolecular Michael reactions cata- a decisive role in helping the reaction to pro- lysed by cysteine-derived catalyst. ceed. One important example is the use of (S)-2- [ b i s ( 3 , 5 - b i s t r i fl uoromethylphenyl) 54 Yang et al. also utilized MacMillan imida- trimethylsilanyloxymethyl]pyrrolidine (27) for zolidinium salt for reductive Michael cyclisation Michael addition of various aldehydes to nitro of enal enones in the presence of Hantzsch ester olefins, which was reported by Hayashi et al. as hydrogen donor, leading to the development (Scheme 17).22k The catalysts was synthesised of the corresponding keto aldehydes with high from a commercially available diphenylprolinol enantioselectivity (Scheme 16). in a single step, and the products were obtained in nearly optically pure form in almost all the COR1 2 1 cases examined. Some other importantO organo- R COR EtO2C CO2Et 29 20 mol% R2 N + catalysts used for asymmetric Michael additiont-Bu o CHO Dioxaneof, 2 0 carbonyl C compounds to nitroB n olefinsN are CHO N 1 H COHR 2 1 O shown in Figure 3. R COR EtO2C CO2Et 29 20 mol% R2 N Yield = Upto 98% 29 + t-Bu de = Upto 96% o CHO Dioxane, 20 C Bn N ee = Upto 97% CHO N H H Yield = Upto 98% 29 de = Upto 96% 130 ee = Upto 97% Vanlaldinpuia and Lalthanpuii

O O O OAr Ar 27 1207-2 100 m-2o0l %mol% + +Ar Ar NO2NO2 H H NO2NO2 H H HexaHneex,a 0n eo,C 0 oC R R R R YieldY i=e lUd p=t oU 8p5to% 85% de =d Ue p=t oU 9p2to% 92% ee =e Ue p=t oU 9p9to% 99%

Scheme 17. Asymmetric Michael addition using organocatalyst 27.

CF3 O S TfHN

NHSO2n-C4F9 N N N CF3 OTBDMS HO N H H NH H NH N H 28 29 30 31 N CF 3 O O N H O N N N H S CF N O N NH N 3 HO H O N H O 32 33 34

Figure 3. Some organocatalysts used for Michael addition of to nitro olefins.

CONCLUSION ACKNOWLEDGEMENT

Organocatalysis have recently emerged as The author (KVL) gratefully acknowledges one of the most useful methods for the synthesis UGC, Government of India (Grant No: UGC of asymmetric compounds. Their reactivity, ease F.No.- 43-210/2014(SR) for financial support. of handling and mild reaction condition makes them a reasonable platform for the development REFERENCES of new powerful transformation. As it is shown in this review, many different types of asymmet- 1. Perlmutter, P (1992). Conjugate Addition Reactions in Organic ric catalysts were developed from organic Synthesis. Pergamon Press, Oxford, pp. 1–4. sources for different asymmetric Michael addi- 2. Michael A (1887). Ueber die Addition von Natriumacetes- tion reactions. Although the highlighted meth- sigund Natriummalonsaureathern zu den Aethern unge- odologies may have several drawbacks such as sattiger Sauren. J Prak. Chem, 35, 349–356. high catalytic loading and unfavourable reaction 3. Tokoroyama T (2010). Discovery of the Michael reaction. conditions, the achievements with these method- Eur J Org Chem, 10, 2009–2016. ologies are immense and many improvements 4. Conrad M & Guthzeit M (1884). Uber die Einwirkung are expected in the future. von α,β-Dibromopropionsaure auf Malonsaureester. Ber Dtsch Chem Ges, 17, 1185–1188. 5. Claisen RL (1887). Bemerkung uber die addition von

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