Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• the authors to propose that the first stage of the reaction would be the insertion of carbon monoxide into the Ar–I bond to produce aryl iodide 107, followed by the reaction with the nitrogen nucleophile to form amide intermediate 108. Finally, intramolecular Michael addition would furnish lactam unit

• involving a sequential enamine formation-Michael addition to produce intermediate 139, followed by intramolecular cyclization to 141 and aromatization through species 142 and 143 (Scheme 40). The cyclization step takes place in a regioselective manner, leading to five-membered heterocycle 141 rather than to

Efficient synthesis of pyrazolopyridines containing a chromane backbone through domino reaction

• Razieh Navari,
• Saeed Balalaie,
• Saber Mehrparvar,
• Fatemeh Darvish,
• Frank Rominger,
• Fatima Hamdan and
• Sattar Mirzaie

Beilstein J. Org. Chem. 2019, 15, 874–880, doi:10.3762/bjoc.15.85

• -one as a suitable Michael acceptor that can react with benzylamine or any primary amine to produce the intermediate A. There is a conjugated system in intermediate A that allows malononitrile to attack through Michael addition and produces the intermediate B (Scheme 2). Due to the presence of acidic

An efficient synthesis of the guaiane sesquiterpene (−)-isoguaiene by domino metathesis

• Yuzhou Wang,
• Ahmed F. Darweesh,
• Patrick Zimdars and
• Peter Metz

Beilstein J. Org. Chem. 2019, 15, 858–862, doi:10.3762/bjoc.15.83

• ; metathesis; Michael addition; organocatalysis; terpenes; Introduction The guaiane sesquiterpene (−)-isoguaiene (1) has been isolated from the liverworts Pellia epiphylla [1] and Dumortiera hirsuta [2] as well as from several Pimpinella species [3][4], while the (+)-enantiomer of 1 has been isolated from the

• feature a domino metathesis event and an organocatalytic Michael addition as the key steps. In closer analogy to our improved synthesis of clavukerin A (2) [8], a relay metathesis [9] of trienyne 3 was expected to lead to the hydroazulene 1 selectively. Trienyne 3 was envisioned to result from a

• stereoselective Michael addition of aldehyde 4 to methyl vinyl ketone [7][8][10] followed by chemoselective elaboration of the two carbonyl functions. Finally, aldehyde 4 was traced back to the commercially available starting material (S)-citronellal (5). On the other hand, a more rarely used enediyne metathesis

Mn-mediated sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction towards annulated imidazo[1,2-a]pyridines

• Olga A. Storozhenko,
• Alexey A. Festa,
• Delphine R. Bella Ndoutoume,
• Alexander V. Aksenov,
• Alexey V. Varlamov and
• Leonid G. Voskressensky

Beilstein J. Org. Chem. 2018, 14, 3078–3087, doi:10.3762/bjoc.14.287

• proceeds through a domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction sequence. Keywords: 2-aminochromene; domino reaction; imidazo[1,2-a]pyridine; 2-iminochromene; Michael addition; multicomponent reaction; oxidation; pyridine amination; Introduction Domino reactions are well

• . Subsequent treatment of the reaction mixture with nucleophile, oxidant and a base leads to the Michael addition on C(4) of the chromene ring to produce 2-aminochromene B with incorporated nucleophilic moiety. Further cyclization and deprotonation furnishes anion C, which is easily oxidized to final product 5

• conclusion, we have developed a practical route towards substituted chromenoimidazopyridines through a sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction, employing cheap and abundant oxidants. The discovered process works in a broad substrate scope with

Nucleofugal behavior of a β-shielded α-cyanovinyl carbanion

• Rudolf Knorr and
• Barbara Schmidt

Beilstein J. Org. Chem. 2018, 14, 3018–3024, doi:10.3762/bjoc.14.281

• Rudolf Knorr Barbara Schmidt Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5–13 (Haus F), 81377 München, Germany 10.3762/bjoc.14.281 Abstract Sterically well-shielded against unsolicited Michael addition and polymerization reactions, α-metalated α-(1,1,3,3

Synthesis of indole–cycloalkyl[b]pyridine hybrids via a four-component six-step tandem process

• Muthumani Muthu,
• Rakkappan Vishnu Priya,
• Abdulrahman I. Almansour,
• Raju Suresh Kumar and
• Raju Ranjith Kumar

Beilstein J. Org. Chem. 2018, 14, 2907–2915, doi:10.3762/bjoc.14.269

• condensation–nucleophilic addition to carbonyl–Michael addition–N-cyclization–elimination–air oxidation sequence to afford structurally intriguing indole–cycloalkyl[b]pyridine-3-carbonitrile hybrid heterocycles in excellent yields. Keywords: cycloalkyl[b]pyridine-3-carbonitrile; cyclododecanone; 3-(1H-indol-3

• formation of (E)-3-(4-chlorophenyl)-2-(1H-indole-3-carbonyl)acrylonitrile (8). Simultaneously, the reaction of cyclododecanone (5a) with ammonium acetate affords the enamine 9. The Michael addition of 8 and the enamine 9 yields the intermediate 10. Then the amino group of 10 undergoes intramolecular

Microfluidic light-driven synthesis of tetracyclic molecular architectures

• Javier Mateos,
• Nicholas Meneghini,
• Marcella Bonchio,
• Nadia Marino,
• Tommaso Carofiglio,
• Xavier Companyó and
• Luca Dell’Amico

Beilstein J. Org. Chem. 2018, 14, 2418–2424, doi:10.3762/bjoc.14.219

• Michael addition pathway (see Figure 1b) [6]. Prompted by the interest of developing novel light-driven microfluidic methods for the construction of biologically relevant molecular scaffolds, we investigated the reaction between MBP 1 and 3-unsubstituted coumarin (2a) and chromone (3a, Figure 1c). It was

• through a [4 + 2] cycloaddition manifold. b) Light-driven reaction between 2-MBP A and 3-substituted coumarin D for the synthesis of E through a Michael addition manifold. c) Light-driven reaction between 2-MBPs 1 and coumarin (2a) or chromone (3a) for the synthesis of privileged tetracyclic scaffolds 4

Synthesis and post-functionalization of alternate-linked-meta-para-[2ⁿ.1ⁿ]thiacyclophanes

• Wout De Leger,
• Koen Adriaensen,
• Koen Robeyns,
• Luc Van Meervelt,
• Joice Thomas,
• Björn Meijers,
• Mario Smet and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2190–2197, doi:10.3762/bjoc.14.192

• deprotonation of the OH group and subsequent chloride loss of 4 an o-quinoid structure 9 is formed in situ, that quickly reacts with the deprotonated thiol 10 via Michael addition (Scheme 3, route A) [28][29][30]. However, as aromatic thiols at the benzylic position are good leaving groups, conversely β

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• reaction stream containing Michael addition product is mixed with hydrogen gas (from H2 cylinder) in mixer M7. The resulting two-phase mixture can be passed to reactor R7 packed with Pd/DMPSi-C catalyst and maintained at 100 °C. The reaction stream can then be passed in intermediate tank T7 where unreacted

Asymmetric Michael addition reactions catalyzed by calix[4]thiourea cyclohexanediamine derivatives

• Zheng-Yi Li,
• Hong-Xiao Tong,
• Yuan Chen,
• Hong-Kui Su,
• Tangxin Xiao,
• Xiao-Qiang Sun and
• Leyong Wang

Beilstein J. Org. Chem. 2018, 14, 1901–1907, doi:10.3762/bjoc.14.164

• Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China 10.3762/bjoc.14.164 Abstract A number of upper rim-functionalized calix[4]thiourea cyclohexanediamine derivatives have been designed, synthesized and used as catalysts for enantioselective Michael addition reactions between

• clearly showed that the upper rim-functionalized hydrophobic calixarene scaffold played an important role in cooperation with the catalytic center to the good reactivities and enantioselectivities. Keywords: asymmetric Michael addition reaction; calix[4]arene; cyclohexanediamine; thiourea; Introduction

• convenience and good stereoselectivity [5][6]. Accordingly, different versions of this reaction have been extensively studied. Notably, the Michael addition reaction of 1,3-dicarbonyl compounds to conjugated nitroalkenes is very important for the synthesis of chiral nitro carbonyl compounds, such as bioactive

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• reaction in the following order: phase-transfer catalysis, Henry reaction, Suzuki–Miyaura cross-coupling and Tsuji–Trost allylic substitution, hydrogenation, Michael addition, aldol and multicomponent Biginelli reactions, epoxidation, Meerwein−Ponndorf−Verley reduction, aza-Diels−Alder and epoxide ring

• conformationally rigid calixarenes were used. Hydrogenation of 41a catalyzed by Rh/40b yielded (R)-42a quantitatively with 98% ee. The high catalytic activity of ligands 40 could be ascribed to combining of an effective bite-angle control with that of circular rigid platform. Michael addition It is known that the

• asymmetric Michael addition reaction of thiophenol could be catalyzed by inherently chiral calixarenes bearing amino alcohol/phenol structure [47][48]. In order to see the effect of the diarylmethanol moiety, Shirakawa and Shimizu used 43 (Figure 6) as organocatalyst in the Michael addition reaction between

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

Methyl isocyanide as a convertible functional group for the synthesis of spirocyclic oxindole γ-lactams via post-Ugi-4CR/transamidation/cyclization in a one-pot, three-step sequence

• Amarendar Reddy Maddirala and
• Peter R. Andreana

Beilstein J. Org. Chem. 2018, 14, 875–883, doi:10.3762/bjoc.14.74

• cyclization product 7a and not the 4-exo-dig-cyclization compound 7a' (Scheme 3). We rationalized, as per Baldwin’s rules, that the 5-endo-dig cyclization of a 1,4-Michael addition was more favorable than the 4-exo-dig-cyclization [50][51]. The structure of compound 7a was definitively confirmed by X-ray

• a 1,4-Michael addition to form an exclusive 5-endo-trig cyclization of 5-chloro-1'-phenylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8a, Scheme 5). Compound 8a was unequivocally confirmed by both, mass spectral analysis and NMR. Encouraged by the results, we prepared a library of spiro[indoline-3,2

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• medicines and can be obtained by organocatalytic Michael additions. We show here the stereoselective synthesis of 4-methylpregabalin stereoisomers using a Michael addition of dimethyl malonate to a racemic nitroalkene. The key step of the synthesis operates as a kinetic resolution with a chiral squaramide

• catalyst. Furthermore, specific organocatalysts can provide respective stereoisomers of the key Michael adduct in up to 99:1 er. Keywords: kinetic resolution; Michael addition; organocatalysis; pregabalin; squaramide; Introduction Asymmetric organocatalysis has considerably broadened possibilities for

• . Stereoselective Michael addition, one of the most important organocatalytic reactions [8] usually serves as a key stereoinduction transformation. Earlier studies, performed by Hayashi and Wang employed iminium activation to perform the enantioselective addition of nitromethane to enals for syntheses of baclofen

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• extended backbone at the ligation site [91]. Examples of the fluorogenic templated ligation of PNA are given in Table 1 which include the simple native chemical ligation of two fluorophore-labeled probes [92], formation of cyanine dyes [93][94], fluorogenic Michael addition [95][96] and cross-linking of

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• ) and α,β-unsaturated ketones 24 (Scheme 3) in the ionic solvent [bmim]Br at 90 °C with excellent yield. Variation of the aryl substituents on the α,β-unsaturated ketones 24 has no significant effect on the reaction. The reaction was proposed to occur through a sequence of Michael addition, cyclization

• = tert-butyl) the reaction results in the formation of pyrazolo[1,5-a]pyrimidine derivative 90 as an additional product. The authors proposed that the bulky group had significantly slowed down the rate of electrophilic aromatic substitution at C-4 on 1H-pyrazol-5-amine due to which the aza-Michael

• addition becomes competitive at N-1 which ultimately provides pyrazolo[1,5-a]pyrimidine derivative 90 as additional product (Scheme 25). The synthesized pyrazolo[3,4-b]pyridines 89 were found to be good mGluR5 positive allosteric modulators (PAMs) and therefore can be used to develop antipsychotic drugs to

Gram-scale preparation of negative-type liquid crystals with a CF₂CF₂-carbocycle unit via an improved short-step synthetic protocol

• Tatsuya Kumon,
• Shohei Hashishita,
• Takumi Kida,
• Shigeyuki Yamada,
• Takashi Ishihara and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 148–154, doi:10.3762/bjoc.14.10

• addition reaction, a Michael addition reaction, giving rise to the corresponding magnesium enolate Int-L. The subsequent hydrolysis of Int-L then leads to the γ-hydroxyketone 8a', which easily tautomerizes into the more stable 5-membered hemiacetal 8a. From the above insight into the reaction mechanism, if

Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications

• Mattias Bood,
• Sangamesh Sarangamath,
• Moa S. Wranne,
• Morten Grøtli and
• L. Marcus Wilhelmsson

Beilstein J. Org. Chem. 2018, 14, 114–129, doi:10.3762/bjoc.14.7

• ammonia in MeOH, followed by cyclization by refluxing deprotected 8 with KF in EtOH. Presumably, a transient Michael addition of the hydroxy group to the C6 position of compound 6 increases the reactivity of the C5 position towards substitution. Standard dimethoxytritylation of compounds 7 and 8 furnished

From dipivaloylketene to tetraoxaadamantanes

• Gert Kollenz and
• Curt Wentrup

Beilstein J. Org. Chem. 2018, 14, 1–10, doi:10.3762/bjoc.14.1

• reaction (Scheme 7), and not in the final products, which are not prone to decarboxylation: the stable bis-carboxylic acid 24 can be obtained by hydrogenolysis of the dibenzyl ester 23 (Scheme 6) [30]. The reaction may be seen as a decarboxylative [31][32] oxa-Michael addition (Scheme 7) and may be related

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• (α-styryl)furan (47) with dimethyl dicyanofumarate (E-1b). Acid-catalyzed Michael addition of enolizable ketones of type 49 to E-1. Reaction of diethyl dicyanofumarate (E-1a) with ammonia NH3. Reaction of dialkyl dicyanofumarates E-1 with primary and secondary amines. Reaction of dialkyl

• perhydroquinoxaline derivative 73. Synthesis of ethyl 7-aminopteridin-6-carboxylates 75 via a domino reaction. Synthesis of morhpolin-2-ones 80 from E-1 and β-aminoalcohols 78 through an initial aza-Michael addition and subsequent heterocyclization step. Reaction of 3-amino-5-arylpyrazoles 81 with dialkyl

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

• Yaroslav D. Boyko,
• Valentin S. Dorokhov,
• Alexey Yu. Sukhorukov and
• Sema L. Ioffe

Beilstein J. Org. Chem. 2017, 13, 2214–2234, doi:10.3762/bjoc.13.220

• 10.3762/bjoc.13.220 Abstract Despite of their chemical instability and high reactivity, conjugated nitrosoalkenes are useful intermediates in target-oriented organic synthesis. The present review deals with carbon–carbon bond forming reactions involving Michael addition to α-nitrosoalkenes with a

• particular focus on recent developments in this methodology and its use in total synthesis. Keywords: carbon–carbon bond formation; Michael addition; nitrosoalkenes; oximes; total synthesis; Introduction Conjugated nitrosoalkenes (NSA) are close analogs of α-nitroalkenes, which are important Michael

• , Michael addition of C-nucleophiles to α-nitrosoalkenes opens access to synthetically valuable α-branched oximes, which can be further utilized as useful intermediates in total synthesis. The high potential of this carbon–carbon bond-forming strategy has been recognized since 1970s in works of Corey

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• depolymerization of cellulose [18] and the synthesis of dihydropyrimidine derivatives [19]. The monosodium salt of phosphonic acids were also employed as organocatalysts for Michael addition [20]. The capacity of phosphonic acids to increase the solubility of organic compounds in water was employed to develop

Regiodivergent condensation of 5-alkoxycarbonyl-1H-pyrrol-2,3-diones with cyclic ketazinones en route to spirocyclic scaffolds

• Alexey Yu. Dubovtsev,
• Maksim V. Dmitriev,
• Аndrey N. Maslivets and
• Michael Rubin

Beilstein J. Org. Chem. 2017, 13, 2179–2185, doi:10.3762/bjoc.13.218

• cyclocondensation of six-membered cyclic enamines 1 (vinylogous secondary amides) with 5-methoxycarbonyl-1H-pyrrolediones 2 [39][40][41]. This transformation involved the Michael addition of an enamine to the α,β-unsaturated carbonyl fragment of a pyrroledione and subsequent 5-exo-trig intramolecular nucleophilic

• involving Michael addition followed by intramolecular transesterification. Remarkably, the resulting bridged products 12 have reversed regiochemistry as compared to the earlier-described cycloadducts 5 (Scheme 1). It should also be pointed out that all of these products were formed as single 10-endo