Michael addition reaction

Last updated

Contents

Michael Addition
Reaction type Addition reaction
Reaction
Michael Donor
+
Michael Acceptor
+
(H3O+)
↓
Michael adduct
Identifiers
Organic Chemistry Portal michael-addition
RSC ontology ID RXNO:0000009

In organic chemistry, the Michael reaction or Michael 1,4 addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon-carbon bond at the acceptor's β-carbon. [1] [2] It belongs to the larger class of conjugate additions and is widely used for the mild formation of carbon-carbon bonds. [3]

Michael 1,4 reaction equation.svg

The Michael addition is an important atom-economical method for diastereoselective and enantioselective C–C bond formation, and many asymmetric variants exist [4] [5] [6]

In this general Michael addition scheme, either or both of R and R' on the nucleophile (the Michael donor) represent electron-withdrawing substituents such as acyl, cyano, nitro, or sulfone groups, which make the adjacent methylene hydrogen acidic enough to form a carbanion when reacted with the base, B:. For the alkene (the Michael acceptor), the R" substituent is usually a carbonyl, which makes the compound an α,β-unsaturated carbonyl compound (either an enone or an enal), or R" may be any electron withdrawing group.

Michael Reaction general.svg

Definition

As originally defined by Arthur Michael, [7] [8] the reaction is the addition of an enolate of a ketone or aldehyde to an α,β-unsaturated carbonyl compound at the β carbon. The current definition of the Michael reaction has broadened to include nucleophiles other than enolates. [9] Some examples of nucleophiles include doubly stabilized carbon nucleophiles such as beta-ketoesters, malonates, and beta-cyanoesters. The resulting product contains a highly useful 1,5-dioxygenated pattern. Non-carbon nucleophiles such as water, alcohols, amines, and enamines can also react with an α,β-unsaturated carbonyl in a 1,4-addition. [10]

Some authors have broadened the definition of the Michael addition to essentially refer to any 1,4-addition reaction of α,β-unsaturated carbonyl compounds. Others, however, insist that such a usage is an abuse of terminology, and limit the Michael addition to the formation of carbon–carbon bonds through the addition of carbon nucleophiles. The terms oxa-Michael reaction and aza-Michael reaction [2] have been used to refer to the 1,4-addition of oxygen and nitrogen nucleophiles, respectively. The Michael reaction has also been associated with 1,6-addition reactions. [11]

Mechanism

In the reaction mechanism, there is 1 as the nucleophile: [3]

Arrow pushing mechanism of Micheal reaction.png

Deprotonation of 1 by a base leads to carbanion 2, stabilized by its electron-withdrawing groups. Structures 2a to 2c are three resonance structures that can be drawn for this species, two of which have enolate ions. This nucleophile reacts with the electrophilic alkene 3 to form 4 in a conjugate addition reaction. Finally, enolate 4 abstracts a proton from protonated base (or solvent) to produce 5.

The reaction is dominated by orbital, rather than electrostatic, considerations. The HOMO of stabilized enolates has a large coefficient on the central carbon atom while the LUMO of many alpha, beta unsaturated carbonyl compounds has a large coefficient on the beta carbon. Thus, both reactants can be considered soft. These polarized frontier orbitals are of similar energy, and react efficiently to form a new carbon–carbon bond. [12]

Like the aldol addition, the Michael reaction may proceed via an enol, silyl enol ether in the Mukaiyama–Michael addition, or more usually, enolate nucleophile. In the latter case, the stabilized carbonyl compound is deprotonated with a strong base (hard enolization) or with a Lewis acid and a weak base (soft enolization). The resulting enolate attacks the activated olefin with 1,4-regioselectivity, forming a carbon–carbon bond. This also transfers the enolate to the electrophile. Since the electrophile is much less acidic than the nucleophile, rapid proton transfer usually transfers the enolate back to the nucleophile if the product is enolizable; however, one may take advantage of the new locus of nucleophilicity if a suitable electrophile is pendant. Depending on the relative acidities of the nucleophile and product, the reaction may be catalytic in base. In most cases, the reaction is irreversible at low temperature.

History

The research done by Arthur Michael in 1887 at Tufts University was prompted by an 1884 publication by Conrad & Kuthzeit on the reaction of ethyl 2,3-dibromopropionate with diethyl sodiomalonate forming a cyclopropane derivative [13] (now recognized as involving two successive substitution reactions).

Michael reaction Conrad Guthzeit comparison.svg

Michael was able to obtain the same product by replacing the propionate by 2-bromacrylic acid ethylester and realized that this reaction could only work by assuming an addition reaction to the double bond of the acrylic acid. He then confirmed this assumption by reacting diethyl malonate and the ethyl ester of cinnamic acid forming the first Michael adduct: [14]

Original Michael reaction.svg

In the same year Rainer Ludwig Claisen claimed priority for the invention. [15] He and T. Komnenos had observed addition products to double bonds as side-products earlier in 1883 while investigating condensation reactions of malonic acid with aldehydes. [16] However, according to biographer Takashi Tokoroyama, this claim is without merit. [14]

Asymmetric Michael reaction

Researchers have expanded the scope of Michael additions to include elements of chirality via asymmetric versions of the reaction. The most common methods involve chiral phase transfer catalysis, such as quaternary ammonium salts derived from the Cinchona alkaloids; or organocatalysis, which is activated by enamine or iminium with chiral secondary amines, usually derived from proline. [17]

In the reaction between cyclohexanone and β-nitrostyrene sketched below, the base proline is derivatized and works in conjunction with a protic acid such as p-toluenesulfonic acid: [18]

Michael reaction asymmetric.png

Syn addition is favored with 99% ee. In the transition state believed to be responsible for this selectivity, the enamine (formed between the proline nitrogen and the cycloketone) and β-nitrostyrene are co-facial with the nitro group hydrogen bonded to the protonated amine in the proline side group.

AsymmetricMichaelTransitionState.png

A well-known Michael reaction is the synthesis of warfarin from 4-hydroxycoumarin and benzylideneacetone first reported by Link in 1944: [19]

Warfarin synthesis.svg

Several asymmetric versions of this reaction exist using chiral catalysts. [20] [21] [22] [23] [24] [25]

Examples

Classical examples of the Michael reaction are the reaction between diethyl malonate (Michael donor) and diethyl fumarate (Michael acceptor), [26] that of diethyl malonate and mesityl oxide (forming Dimedone), [27] that of diethyl malonate and methyl crotonate, [28] that of 2-nitropropane and methyl acrylate, [29] that of ethyl phenylcyanoacetate and acrylonitrile [30] and that of nitropropane and methyl vinyl ketone. [31]

A classic tandem sequence of Michael and aldol additions is the Robinson annulation.

Mukaiyama-Michael addition

In the Mukaiyama–Michael addition, the nucleophile is a silyl enol ether and the catalyst is usually titanium tetrachloride: [32] [33]

Mukaiyama-Michael addition Mukaiyama-Michael addition.png
Mukaiyama–Michael addition

1,6-Michael reaction

The 1,6-Michael reaction proceeds via nucleophilic attack on the 𝛿 carbon of an α,β-,𝛿-diunsaturated Michael acceptor. [34] [35] The 1,6-addition mechanism is similar to the 1,4-addition, with one exception being the nucleophilic attack occurring at the 𝛿 carbon of the Michael acceptor. [35] However, research shows that organocatalysis often favours the 1,4-addition. [34] In many syntheses where 1,6-addition was favoured, the substrate contained certain structural features. [35] Research has shown that catalysts can also influence the regioselectivity and enantioselectivity of a 1,6-addition reaction. [35]

For example, the image below shows the addition of ethylmagnesium bromide to ethyl sorbate 1 using a copper catalyst with a reversed josiphos (R,S)-(–)-3 ligand. [35] This reaction produced the 1,6-addition product 2 in 0% yield, the 1,6-addition product 3 in approximately 99% yield, and the 1,4-addition product 4 in less than 2% yield. This particular catalyst and set of reaction conditions led to the mostly regioselective and enantioselective 1,6-Michael addition of ethyl sorbate 1 to product 3.

The Michael addition of ethylmagnesium bromide to ethyl sorbate. 1,6-Michael addition of ethylmagnesium bromide to ethyl sorbate.png
The Michael addition of ethylmagnesium bromide to ethyl sorbate.

Applications

Pharmaceuticals

A Michael reaction is used as a mechanistic step by many covalent inhibitor drugs. Cancer drugs such as ibrutinib, osimertinib, and rociletinib have an acrylamide functional group as a Michael acceptor. The Michael acceptor on the drug reacts with a Michael acceptor in the active site of an enzyme. This is a viable cancer treatment because the target enzyme is inhibited following the Michael reaction. [36]

Polymerization reactions

Mechanism [2]

All polymerization reactions have three basic steps: initiation, propagation, and termination. The initiation step is the Michael addition of the nucleophile to a monomer. The resultant species undergoes a Michael addition with another monomer, with the latter acting as an acceptor. This extends the chain by forming another nucleophilic species to act as a donor for the next addition. This process repeats until the reaction is quenched by chain termination. [37] The original Michael donor can be a neutral donor such as amines, thiols, and alkoxides, or alkyl ligands bound to a metal. [38]

Polymerization mechanism of a Michael addition with a thiol nucleophile Thiol Michael polymerisation.png
Polymerization mechanism of a Michael addition with a thiol nucleophile

Examples

Linear step growth polymerizations are some of the earliest applications of the Michael reaction in polymerizations. A wide variety of Michael donors and acceptors have been used to synthesize a diverse range of polymers. Examples of such polymers include poly(amido amine), poly(amino ester), poly(imido sulfide), poly(ester sulfide), poly(aspartamide), poly(imido ether), poly(amino quinone), poly(enone sulfide) and poly(enamine ketone).

For example, linear step growth polymerization produces the redox active poly(amino quinone), which serves as an anti-corrosion coatings on various metal surfaces. [39] Another example includes network polymers, which are used for drug delivery, high performance composites, and coatings. These network polymers are synthesized using a dual chain growth, photo-induced radical and step growth Michael addition system.

Poly(amino quinone) Poly amino quinone.png
Poly(amino quinone)
Poly(amido amine) Poly(amido amine).png
Poly(amido amine)

Related Research Articles

<span class="mw-page-title-main">Ketone</span> Organic compounds of the form >C=O

In organic chemistry, a ketone is an organic compound with the structure R−C(=O)−R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group −C(=O)−. The simplest ketone is acetone, with the formula (CH3)2CO. Many ketones are of great importance in biology and in industry. Examples include many sugars (ketoses), many steroids, and the solvent acetone.

The aldol reaction is a reaction that combines two carbonyl compounds to form a new β-hydroxy carbonyl compound.

<span class="mw-page-title-main">Enamine</span> Class of chemical compounds

An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.

<span class="mw-page-title-main">Aldol condensation</span> Type of chemical reaction

An aldol condensation is a condensation reaction in organic chemistry in which two carbonyl moieties react to form a β-hydroxyaldehyde or β-hydroxyketone, and this is then followed by dehydration to give a conjugated enone.

<span class="mw-page-title-main">Organolithium reagent</span> Chemical compounds containing C–Li bonds

In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

The Robinson annulation is a chemical reaction used in organic chemistry for ring formation. It was discovered by Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds. The method uses a ketone and a methyl vinyl ketone to form an α,β-unsaturated ketone in a cyclohexane ring by a Michael addition followed by an aldol condensation. This procedure is one of the key methods to form fused ring systems.

<span class="mw-page-title-main">Enolate</span> Organic anion formed by deprotonating a carbonyl (>C=O) compound

In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.

In organic chemistry, the Knoevenagel condensation reaction is a type of chemical reaction named after German chemist Emil Knoevenagel. It is a modification of the aldol condensation.

The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base. The reaction produces a β-keto ester or a β-diketone. It is named after Rainer Ludwig Claisen, who first published his work on the reaction in 1887. The reaction has often been displaced by diketene-based chemistry, which affords acetoacetic esters.

<span class="mw-page-title-main">Nucleophilic conjugate addition</span> Organic reaction

Nucleophilic conjugate addition is a type of organic reaction. Ordinary nucleophilic additions or 1,2-nucleophilic additions deal mostly with additions to carbonyl compounds. Simple alkene compounds do not show 1,2 reactivity due to lack of polarity, unless the alkene is activated with special substituents. With α,β-unsaturated carbonyl compounds such as cyclohexenone it can be deduced from resonance structures that the β position is an electrophilic site which can react with a nucleophile. The negative charge in these structures is stored as an alkoxide anion. Such a nucleophilic addition is called a nucleophilic conjugate addition or 1,4-nucleophilic addition. The most important active alkenes are the aforementioned conjugated carbonyls and acrylonitriles.

In organic chemistry, umpolung or polarity inversion is the chemical modification of a functional group with the aim of the reversal of polarity of that group. This modification allows secondary reactions of this functional group that would otherwise not be possible. The concept was introduced by D. Seebach and E.J. Corey. Polarity analysis during retrosynthetic analysis tells a chemist when umpolung tactics are required to synthesize a target molecule.

<span class="mw-page-title-main">Darzens reaction</span>

The Darzens reaction is the chemical reaction of a ketone or aldehyde with an α-haloester in the presence of a base to form an α,β-epoxy ester, also called a "glycidic ester". This reaction was discovered by the organic chemist Auguste Georges Darzens in 1904.

In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group R3Si−O−CR=CR2, composed of an enolate bonded to a silane through its oxygen end and an ethene group as its carbon end. They are important intermediates in organic synthesis.

Selenoxide elimination is a method for the chemical synthesis of alkenes from selenoxides. It is most commonly used to synthesize α,β-unsaturated carbonyl compounds from the corresponding saturated analogues. It is mechanistically related to the Cope reaction.

Vicinal difunctionalization refers to a chemical reaction involving transformations at two adjacent centers. This transformation can be accomplished in α,β-unsaturated carbonyl compounds via the conjugate addition of a nucleophile to the β-position followed by trapping of the resulting enolate with an electrophile at the α-position. When the nucleophile is an enolate and the electrophile a proton, the reaction is called Michael addition.

Carbonyl oxidation with hypervalent iodine reagents involves the functionalization of the α position of carbonyl compounds through the intermediacy of a hypervalent iodine(III) enolate species. This electrophilic intermediate may be attacked by a variety of nucleophiles or undergo rearrangement or elimination.

The Juliá–Colonna epoxidation is an asymmetric poly-leucine catalyzed nucleophilic epoxidation of electron deficient olefins in a triphasic system. The reaction was reported by Sebastian Juliá at the Chemical Institute of Sarriá in 1980, with further elaboration by both Juliá and Stefano Colonna.

α,β-Unsaturated carbonyl compound Functional group of organic compounds

α,β-Unsaturated carbonyl compounds are organic compounds with the general structure (O=CR)−Cα=Cβ-R. Such compounds include enones and enals, but also carboxylic acids and the corresponding esters and amides. In these compounds the carbonyl group is conjugated with an alkene. Unlike the case for carbonyls without a flanking alkene group, α,β-unsaturated carbonyl compounds are susceptible to attack by nucleophiles at the β-carbon. This pattern of reactivity is called vinylogous. Examples of unsaturated carbonyls are acrolein (propenal), mesityl oxide, acrylic acid, and maleic acid. Unsaturated carbonyls can be prepared in the laboratory in an aldol reaction and in the Perkin reaction.

The ketimine Mannich reaction is an asymmetric synthetic technique using differences in starting material to push a Mannich reaction to create an enantiomeric product with steric and electronic effects, through the creation of a ketimine group. Typically, this is done with a reaction with proline or another nitrogen-containing heterocycle, which control chirality with that of the catalyst. This has been theorized to be caused by the restriction of undesired (E)-isomer by preventing the ketone from accessing non-reactive tautomers. Generally, a Mannich reaction is the combination of an amine, a ketone with a β-acidic proton and aldehyde to create a condensed product in a β-addition to the ketone. This occurs through an attack on the ketone with a suitable catalytic-amine unto its electron-starved carbon, from which an imine is created. This then undergoes electrophilic addition with a compound containing an acidic proton. It is theoretically possible for either of the carbonyl-containing molecules to create diastereomers, but with the addition of catalysts which restrict addition as of the enamine creation, it is possible to extract a single product with limited purification steps and in some cases as reported by List et al.; practical one-pot syntheses are possible. The process of selecting a carbonyl-group gives the reaction a direct versus indirect distinction, wherein the latter case represents pre-formed products restricting the reaction's pathway and the other does not. Ketimines selects a reaction group, and circumvent a requirement for indirect pathways.

<span class="mw-page-title-main">Jirō Tsuji</span> Japanese chemist (1927–2022)

Jiro Tsuji was a Japanese chemist, notable for his discovery of organometallic reactions, including the Tsuji-Trost reaction, the Tsuji-Wilkinson decarbonylation, and the Tsuji-Wacker reaction.

References

  1. ↑ Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. (1995). "The Intramolecular Michael Reaction". Org. React. Vol. 47. pp. 315–552. doi:10.1002/0471264180.or047.02. ISBN   978-0-471-26418-7.
  2. 1 2 3 Mather, B.; Viswanathan, K.; Miller, K.; Long, T. (2006). "Michael addition reactions in macromolecular design for emerging technologies". Progress in Polymer Science. 31 (5): 487–531. doi:10.1016/j.progpolymsci.2006.03.001.
  3. 1 2 Michael Addition | PharmaXChange.info
  4. ↑ Hunt, I. "Chapter 18: Enols and Enolates – The Michael Addition reaction". University of Calgary.
  5. ↑ Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2001). Organic Chemistry (1st ed.). Oxford University Press. ISBN   978-0-19-850346-0.
  6. ↑ Tiano, Martin (2020). "Enantioselective Michael Addition: An Experimental Introduction to Asymmetric Synthesis". Journal of Chemical Education. 97 (8): 2291–2295. Bibcode:2020JChEd..97.2291T. doi:10.1021/acs.jchemed.0c00164.
  7. ↑ Michael, A. (1887). "Ueber die Addition von Natriumacetessig- und Natriummalonsäureäthern zu den Aethern ungesättigter Säuren" [On the addition of sodium acetoacetate- and sodium malonic acid esters to the esters of unsaturated acids]. Journal für Praktische Chemie. 2nd series. 35: 349–356. doi:10.1002/prac.18870350136.
  8. ↑ Michael, A. (1894). "Ueber die Addition von Natriumacetessig- und Natriummalonsäureäther zu den Aethern ungesättigter Säuren" [On the addition of sodium acetoacetate- and sodium malonic acid esters to the esters of unsaturated acids]. Journal für Praktische Chemie. 2nd series. 49: 20–25. doi:10.1002/prac.18940490103.
  9. ↑ Mather, Brian D.; Viswanathan, Kalpana; Miller, Kevin M.; Long, Timothy E. (1 May 2006). "Michael addition reactions in macromolecular design for emerging technologies". Progress in Polymer Science. 31 (5): 487–531. doi:10.1016/j.progpolymsci.2006.03.001. ISSN   0079-6700.
  10. ↑ Brown, William Henry (2018). Organic chemistry. Brent L. Iverson, Eric V. Anslyn, Christopher S. Foote (Eighth ed.). Boston, Mass. ISBN   978-1-337-51640-2. OCLC   1200494733.{{cite book}}: CS1 maint: location missing publisher (link)
  11. ↑ Guin, Soumitra; Saha, Hemonta K.; Patel, Ashvani K.; Gudimella, Santosh K.; Biswas, Subhankar; Samanta, Sampak (17 July 2020). "1,6-Aza-Michael addition of para-quinone methides with N-heterocycles catalyzed by Zn(OTf)2: A regioselective approach to N-diarylmethyl-substituted heterocycles". Tetrahedron. 76 (28): 131338. doi:10.1016/j.tet.2020.131338. ISSN   0040-4020. S2CID   225589003.
  12. ↑ Perlmutter, P., ed. (1 January 1992), "Chapter One – Introduction", Tetrahedron Organic Chemistry Series, Conjugate Addition Reactions in Organic Synthesis, Elsevier, vol. 9, pp. 1–61, doi:10.1016/b978-0-08-037067-5.50007-2 , retrieved 7 October 2022
  13. ↑ Conrad, M.; Guthzeit, M. (1884). "Ueber die Einwirkung von α-β-Dibrompropionsäure auf Malonsäureester" [On the reaction of 2,3-dibrompropionic acid with [diethyl] malonic acid ester]. Berichte der Deutschen Chemischen Gesellschaft. 17 (1): 1185–1188. doi:10.1002/cber.188401701314.
  14. 1 2 Tokoroyama, T. (2010). "Discovery of the Michael Reaction". European Journal of Organic Chemistry. 2010 (10): 2009–2016. doi:10.1002/ejoc.200901130.
  15. ↑ Claisen, L. (1887). "Bemerkung über die Addition von Aethylmalonat an Körper mit doppelter Kohlenstoffbindung" [Observation on the addition of [di]ethyl malonate to substances with a double carbon bond]. Journal für Praktische Chemie. 2nd series. 35 (1): 413–415. doi:10.1002/prac.18870350144.
  16. ↑ Komnenos, T. (1883). "Ueber die Einwirkung von Fettaldehyden auf Malonsäure und Aethylmalonat" [On the reaction of aliphatic aldehydes with malonic acid and [di]ethylmalonate]. Justus Liebig's Annalen der Chemie. 218 (2): 145–167. doi:10.1002/jlac.18832180204.
  17. ↑ Reyes, E.; Uria, U.; Vicario, J. L.; Carrillo, L. (2016). "The Catalytic, Enantioselective Michael Reaction". Organic Reactions. 90: 1–898. doi:10.1002/0471264180.or090.01. ISBN   9780471264187.
  18. ↑ Pansare, S. V.; Pandya, K. (2006). "Simple Diamine- and Triamine-Protonic Acid Catalysts for the Enantioselective Michael Addition of Cyclic Ketones to Nitroalkenes". Journal of the American Chemical Society. 128 (30): 9624–9625. doi:10.1021/ja062701n. PMID   16866504.
  19. ↑ Ikawa, M.; Stahmann, M. A.; Link, K. P. (1944). "Studies on 4-Hydroxycoumarins. V. The Condensation of α,β-Unsaturated Ketones with 4-Hydroxycoumarin". Journal of the American Chemical Society. 66 (6): 902. doi:10.1021/ja01234a019.
  20. ↑ Halland, N.; Hansen, T.; Jørgensen, K. (2003). "Organocatalytic asymmetric Michael reaction of cyclic 1,3-dicarbonyl compounds and α,β-unsaturated ketones--a highly atom-economic catalytic one-step formation of optically active warfarin anticoagulant". Angewandte Chemie. 42 (40): 4955–4957. doi:10.1002/anie.200352136. PMID   14579449.
  21. ↑ Kim, H.; Yen, C.; Preston, P.; Chin, J. (2006). "Substrate-directed stereoselectivity in vicinal diamine-catalyzed synthesis of warfarin". Organic Letters. 8 (23): 5239–5242. doi:10.1021/ol062000v. PMID   17078687.
  22. ↑ Xie, J.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.; Chen, Y. (2007). "Highly Enantioselective Michael Addition of Cyclic 1,3-Dicarbonyl Compounds to α,β-Unsaturated Ketones". Organic Letters. 9 (3): 413–415. doi:10.1021/ol062718a. PMID   17249775.
  23. ↑ Kristensen, T. E.; Vestli, K.; Hansen, F. K.; Hansen, T. (2009). "New Phenylglycine-Derived Primary Amine Organocatalysts for the Preparation of Optically Active Warfarin". European Journal of Organic Chemistry. 2009 (30): 5185. doi:10.1002/ejoc.200900664.
  24. ↑ Dong, Z.; Wang, L.; Chen, X.; Liu, X.; Lin, L.; Feng, X. (2009). "Organocatalytic Enantioselective Michael Addition of 4-Hydroxycoumarin to α,β-Unsaturated Ketones: A Simple Synthesis of Warfarin". European Journal of Organic Chemistry. 2009 (30): 5192. doi:10.1002/ejoc.200900831.
  25. ↑ Wong, T. C.; Sultana, C. M.; Vosburg, D. A. (2010). "A Green, Enantioselective Synthesis of Warfarin for the Undergraduate Organic Laboratory". Journal of Chemical Education. 87 (2): 194. Bibcode:2010JChEd..87..194W. doi:10.1021/ed800040m.
  26. ↑ Clarke, H. T.; Murray, T. F. (1941). "1,1,2,3-Propanetetracarboxylic acid, tetraethyl ester". Organic Syntheses .; Collective Volume, vol. 1, p. 272
  27. ↑ Shriner, R. L.; Todd, H. R. (1943). "1,3-Cyclohexanedione, 5,5-dimethyl-". Organic Syntheses .; Collective Volume, vol. 2, p. 200
  28. ↑ James Cason (1963). "β-Methylglutaric anhydride". Organic Syntheses .; Collective Volume, vol. 4, p. 630
  29. ↑ Moffett, R. B. (1963). "Methyl γ-Methyl-γ-nitrovalerate". Organic Syntheses .; Collective Volume, vol. 4, p. 652
  30. ↑ Horning, E. C.; Finelli, A. F. (1963). "α-Phenyl-α-carbethoxyglutaronitrile". Organic Syntheses .; Collective Volume, vol. 4, p. 776
  31. ↑ McMurry, J. E.; Melton, J. (1988). "Conversion of Nitro to Carbonyl by Ozonolysis of Nitronates: 2,5-Heptanedione". Organic Syntheses .; Collective Volume, vol. 6, p. 648
  32. ↑ Mukaiyama, T. (1977). "Titanium Tetrachloride in Organic Synthesis [New synthetic methods (21)]". Angew. Chem. Int. Ed. Engl. 16 (12): 817–826. doi:10.1002/anie.197708171.
  33. ↑ Lippert, A. R.; Kaeobamrung, J.; Bode, J. W. (2006). "Synthesis of Oligosubstituted Bullvalones: Shapeshifting Molecules Under Basic Conditions". Journal of the American Chemical Society . 128 (46): 14738–14739. doi:10.1021/ja063900+. PMID   17105247.
  34. 1 2 Hayashi, Yujiro; Okamura, Daichi; Umemiya, Shigenobu; Uchimaru, Tadafumi (July 2012). "Organocatalytic 1,4-Addition Reaction of α,β-γ,δ-Diunsaturated Aldehydes versus 1,6-Addition Reaction". ChemCatChem. 4 (7): 959–962. doi:10.1002/cctc.201200161. S2CID   98643888.
  35. 1 2 3 4 5 den Hartog, Tim; Harutyunyan, Syuzanna R.; Font, Daniel; Minnaard, Adriaan J.; Feringa, Ben L. (January 2008). "Catalytic Enantioselective 1,6-Conjugate Addition of Grignard Reagents to Linear Dienoates". Angewandte Chemie International Edition. 47 (2): 398–401. doi:10.1002/anie.200703702. PMID   18041800.
  36. ↑ Boike, Lydia; Henning, Nathaniel J.; Nomura, Daniel K. (25 August 2022). "Advances in covalent drug discovery". Nature Reviews Drug Discovery. 21 (12): 881–898. doi:10.1038/s41573-022-00542-z. ISSN   1474-1776. PMC   9403961 . PMID   36008483.
  37. ↑ Huang, Sijia; Sinha, Jasmine; Podgórski, Maciej; Zhang, Xinpeng; Claudino, Mauro; Bowman, Christopher N. (14 August 2018). "Mechanistic Modeling of the Thiol–Michael Addition Polymerization Kinetics: Structural Effects of the Thiol and Vinyl Monomers". Macromolecules. 51 (15): 5979–5988. Bibcode:2018MaMol..51.5979H. doi:10.1021/acs.macromol.8b01264. ISSN   0024-9297. S2CID   105834506.
  38. ↑ Jung, Hyuk-Joon; Yu, Insun; Nyamayaro, Kudzanai; Mehrkhodavandi, Parisa (5 June 2020). "Indium-Catalyzed Block Copolymerization of Lactide and Methyl Methacrylate by Sequential Addition". ACS Catalysis. 10 (11): 6488–6496. doi:10.1021/acscatal.0c01365. ISSN   2155-5435. S2CID   219762406.
  39. ↑ Pham, M.C; Hubert, S; Piro, B; Maurel, F; Le Dao, H; Takenouti, H (February 2004). "Investigations of the redox process of conducting poly(2-methyl-5-amino-1,4-naphthoquinone) (PMANQ) film". Synthetic Metals. 140 (2–3): 183–197. doi:10.1016/S0379-6779(03)00373-4.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.