A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

• Seema V. Kanojia,
• Sucheta Chatterjee,
• Subrata Chattopadhyay and
• Dibakar Goswami

Beilstein J. Org. Chem. 2019, 15, 490–496, doi:10.3762/bjoc.15.42

• /aza-Michael reaction of 3,6-dihydro-1,2-dioxines followed by diastereoselective reduction [25]. Most of these methods employ starting materials or catalysts, which are not commercially available, and also require operationally demanding reaction conditions. Hence a need to develop a simple, efficient

DABCO- and DBU-promoted one-pot reaction of N-sulfonyl ketimines with Morita–Baylis–Hillman carbonates: a sequential approach to (2-hydroxyaryl)nicotinate derivatives

• Soumitra Guin,
• Raman Gupta,
• Debashis Majee and
• Sampak Samanta

Beilstein J. Org. Chem. 2018, 14, 2771–2778, doi:10.3762/bjoc.14.254

• ' fashion to make a very reactive allyl ammonium intermediate 6. The latter further involves in the SN2' reaction with in situ generated carbanion intermediate 1a' forming SN2-adduct 3a. It undergoes an intramolecular aza-Michael reaction in the presence of DABCO, leading to tricyclic product 4a. For the

• -hydroxyaryl)pyridine derivatives bearing a carboxylate or a nitrile group suitably placed at C3 position of the aza-ring has been achieved in acceptable chemical yields with a broad functional group tolerance. This sequential C–C/C–N bond making process proceeds through a regioselective allylic alkylation/aza

• -Michael reaction between MBH carbonates derived from an acrylate/acrylonitrile and N-sulfonyl ketimines as C,N-binucleophiles catalyzed by DABCO, followed by elimination of SO2 under the influence of base and subsequent aromatization in an open atmosphere. Keywords: MBH carbonates; metal-free; N-sulfonyl

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

• Pavel Yanev and
• Plamen Angelov

Beilstein J. Org. Chem. 2018, 14, 2602–2606, doi:10.3762/bjoc.14.238

• pyrrolinones 6 were the minor product and the β-keto amides 5a–f were obtained in higher, although still moderate, yields (Table 1). These results indicated that the acidic conditions required for the Boc deprotection favoured the unwanted side process (Scheme 3) and the aza-Michael/retro-Mannich sequence only

• aza-Michael/retro-Mannich domino approach. A competing cyclisation to pyrrolin-4-ones limits the range of accessible γ-amino-derivatives and imposes the requirement for tertiary-substituted nitrogen in the aminoacyl moiety. There is no such limitation for the ω-amino derivatives. Preparation of α-C

Synthesis of cis-hydrindan-2,4-diones bearing an all-carbon quaternary center by a Danheiser annulation

• Gisela V. Saborit,
• Carlos Cativiela,
• Ana I. Jiménez,
• Josep Bonjoch and
• Ben Bradshaw

Beilstein J. Org. Chem. 2018, 14, 2597–2601, doi:10.3762/bjoc.14.237

• , following our previously developed procedure, to give decahydroquinoline 1 [23]. The removal of the tert-butyl ester group with TFA, followed by treatment with LiOH in refluxing THF promoted a retro-aza-Michael reaction yielding the ring-opened product 3 [33]. The latter was trapped in situ with benzyl

• bromide to furnish cyclohexenone 4 in 86% overall yield over the two steps from 1. Additionally, the overall transformation from the starting material 2 was also performed in a one-pot sequence involving six reactions, namely, an intermolecular Michael reaction, aldol cyclization, intramolecular aza

• -Michael reaction, removal of a tert-butoxycarbonyl ester, base-promoted ring opening and tosylamide benzylation, without significant detrimental effect on the overall yield (see Supporting Information File 1). With the key precursor 4 in hand, the stage was set to study the Danheiser annulation step

Atom-economical group-transfer reactions with hypervalent iodine compounds

• Andreas Boelke,
• Peter Finkbeiner and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2018, 14, 1263–1280, doi:10.3762/bjoc.14.108

• and 2-iodomesitylene (2a). Intramolecular cyclization leads to the iminofuranylium intermediate B which affords the cationic isoindolin-1-one structure C via subsequent intramolecular aza-Michael type rearrangement. This intermediate reacts in the final step with the electron-rich 2-iodomesitylene (2a

Diastereoselective auxiliary- and catalyst-controlled intramolecular aza-Michael reaction for the elaboration of enantioenriched 3-substituted isoindolinones. Application to the synthesis of a new pazinaclone analogue

• Romain Sallio,
• Stéphane Lebrun,
• Frédéric Capet,
• Francine Agbossou-Niedercorn,
• Christophe Michon and
• Eric Deniau

Beilstein J. Org. Chem. 2018, 14, 593–602, doi:10.3762/bjoc.14.46

• intramolecular aza-Michael reaction by means of both a chiral auxiliary and a catalyst for stereocontrol is reported for the synthesis of optically active isoindolinones. A selected cinchoninium salt was used as phase-transfer catalyst in combination with a chiral nucleophile, a Michael acceptor and a base to

• provide 3-substituted isoindolinones in good yields and diastereomeric excesses. This methodology was applied to the asymmetric synthesis of a new pazinaclone analogue which is of interest in the field of benzodiazepine-receptor agonists. Keywords: asymmetric organocatalysis; Aza-Michael reaction; phase

• carbon stereocenter alpha to the nitrogen [10][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Though various metal or organic catalysts were used to promote the aza-Michael reaction in different syntheses for the creation of nitrogen–carbon bonds, phase-transfer catalysts were less studied

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

• = 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

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

• 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

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• [24]. Reports of aza-Michael additions occurring in water indicated that the desired 8 could be synthesised under mild conditions, and we therefore decided to adapt these published conditions to larger scale work [25][26]. Initial attempts involving a 1:1 molar mixture of o-toluidine (5) and methyl

• intermediate 7. Synthesis of THQ 10, by initial aza-Michael addition, followed by formation of the tertiary alcohol 9, which was then cyclised with H2SO4. Synthesis of THQ 14 by initial acylation, cyclisation with H2SO4 and reduction with borane·dimethyl sulphide complex. N-Alkylation of 13 and 14. Facile

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• this producing organism, L-arginine is diastereoselectively hydroxylated to afford (3S)-3-hydroxy-L-arginine. The ring-closure reaction then occurs with formal inversion of the β-stereocenter (but quite likely through an aza-Michael addition to the α,β-unsaturated intermediate) [119][120][121]. The

• studies [123][124]. It should also be noted that a biomimetic domino guanidinylation–aza-Michael-addition reaction for the synthesis of the capreomycidine scaffold has been developed, which only furnished the target structures as stereoisomeric mixtures though [125]. The epicapreomycidine-derived

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• it near the enolate. In 2011, You and co-workers described the intramolecular desymmetrization of cyclohexadienones 69 catalyzed by thiourea 71, derived from cinchonine to give a bicyclic system 70 containing two chiral centers, utilizing an aza-Michael reaction (Scheme 24) [34]. The reaction

• constructed via a desymmetrization aza-Michael reaction. That key intermediate 72 was afforded in 91% yield and 97% ee. (Scheme 25). In 2012, Cobb and co-workers developed a novel asymmetric Michael–Michael reaction between nitrohex-4-enoates 73 and nitroolefins 74 to construct a cyclohexene moiety, bearing

• excellent diastereoselectivities (1.2:1–57:1 dr). In 2011, Chen, Xiao and co-workers, based on their previous work [77], described the aza-Michael–Michael cascade between substituted anilines 178 and nitroolefin enoates 172, utilizing a bifunctional cinchonine-derived thiourea 57 (Scheme 58) [79]. The

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• several methods to obtain rac-9 are available [32][33][34][35][36], it is worth noting that the asymmetric synthesis of 9 is one of the major obstacles when targeting the synthesis of chiral isoindolinones. The recently introduced intramolecular aza-Michael reactions of 2-substituted acrylates gave very

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• )-(+)-pseudoephedrine has emerged as a chiral auxiliary for the use in DCA reactions of α,β-unsaturated amides [49][50][51][52][53][54]. Badía and co-workers published a report where they performed aza-Michael additions to various α,β-unsaturated amides attached to (S,S)-(+)-pseudoephedrine [51] (Scheme 5

• opposite face. Prior to the development of the diastereoselective aza-Michael reactions, (S,S)-(+)-pseudoephedrine had been used as a chiral auxiliary for the diastereoselective α-alkylation of amides [55][56][57]. This literature precedent aided in the development of the tandem conjugate addition–α

• environment for the reaction to occur. The first part of this section will focus on the asymmetric 1,4-addition of carbon nucleophiles and the next two parts will discuss the addition of amines (aza-Michael addition) and phosphorous compounds. 2.4.1 Asymmetric 1,4-addition of carbon nucleophiles: Since its

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• 2010, using the bifunctional chiral phosphine G1, bearing both Brønsted acid and Lewis base units, as the catalyst, asymmetric domino aza-MBH/aza-Michael reactions of activated alkenes and N-tosylimines with Michael acceptor moieties at their ortho positions were accomplished to give chiral 1,3

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• post-Ugi cyclization, namely an intramolecular aza-Michael [24] reaction, which afforded compound 18 bearing the privileged spiro-diketopiperazine scaffold (Scheme 2). Spiro-diketopiperazines are present in many natural products [38][39][40] and have recently received much attention as

Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach

• Thi Thanh Huyen Trinh,
• Khanh Hung Nguyen,
• Patricia de Aguiar Amaral and
• Nicolas Gouault

Beilstein J. Org. Chem. 2013, 9, 2042–2047, doi:10.3762/bjoc.9.242

• of (−)-epimyrtine have been described to date including the intramolecular allylsilane N-acyliminium ion cyclization [6], the organocatalytic aza-Michael reaction [7], the intramolecular Mannich reaction [8], and the iminium ion cascade reaction [9][10]. More efficient, convenient and highly

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• 15 by abstraction of a hydrogen atom directly. The addition of the enol form of α-ketoester 59 to 15 furnishes the Mannich adduct 60. A retro-aza-Michael reaction via enol 61 allows cleavage of the C–N bond to yield secondary aniline 62. Aniline 62 is first oxidized to imine 63, which is further

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• reaction of chiral imines with enolates derived from Weinreb amides [13][14]. In previous work on the asymmetric synthesis of 2,6-disubstituted piperidines by C–N bond formation, we demonstrated that intramolecular aza-Michael ”type” cyclisation [15] using a β'-carbamate-α,β-unsaturated ketone

• devised for the asymmetric synthesis of β’-amino-protected-α,β enones, a valuable intermediate for the synthesis of trans 2,6-disubstituted piperidines. The scope and limitation of the aza-Michael reaction were studied with a range of substrates. We are currently working on the application of this

Organocatalytic cascade aza-Michael/hemiacetal reaction between disubstituted hydrazines and α,β-unsaturated aldehydes: Highly diastereo- and enantioselective synthesis of pyrazolidine derivatives

• Zhi-Cong Geng,
• Jian Chen,
• Ning Li,
• Xiao-Fei Huang,
• Yong Zhang,
• Ya-Wen Zhang and
• Xing-Wang Wang

Beilstein J. Org. Chem. 2012, 8, 1710–1720, doi:10.3762/bjoc.8.195

• 65880378 10.3762/bjoc.8.195 Abstract The catalytic synthesis of nitrogen-containing heterocycles is of great importance to medicinal and synthetic chemists, and also a challenge for modern chemical methodology. In this paper, we report the synthesis of pyrazolidine derivatives through a domino aza-Michael

• good results (up to 86% yield, >10/1 regioselectivity, >20:1 dr, 99% ee) in the presence of (S)-diphenylprolinol trimethylsilyl ether catalyst. Keywords: aza-Michael; domino; hydrazine; organocatalysis; pyrazolidine; Introduction Pyrazolidines are privileged and valuable heterocyclic compounds, which

• explored by several groups [72][73]. In 2007, Jørgensen et al. reported that the organocatalyzed asymmetric aza-Michael addition of hydrazones to cyclic enones had been achieved in good yield and stereoselectivity [74]. In 2011, the Deng group developed a highly enantioselective organocatalytic synthesis

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• thiochromenes; and (3) Organocatalytic aza-Michael reactions to access functionalized 1,2-dihydroquinolines, using chiral proline and its derivatives (Figure 2), chiral bifunctional thioureas, cinchona alkaloids and other organocatalysts (Figure 3). For each reaction, the initial screening result of various

• -unsaturated nitro compounds 27 in toluene afforded chiral thiochromans 51 bearing three continuous stereogenic centers with high diastereo- and enantioselectivities by this novel cascade process (Scheme 26). 3. Organocatalytic aza-Michael reactions to access functionalized 1,2-dihydroquinolines 3.1. Reaction

• alcohol. Córdova and co-workers [73] in 2007 first reported an asymmetric organocatalytic tandem aza-Michael–aldol reaction for the synthesis of 1,2-dihydroquinolines through the iminium activation strategy. Thus, the aza-Michael–aldol reaction between 2-aminobenzaldehydes 52 and enals 2 in the presence

A quantitative approach to nucleophilic organocatalysis

• Herbert Mayr,
• Sami Lakhdar,
• Biplab Maji and
• Armin R. Ofial

Beilstein J. Org. Chem. 2012, 8, 1458–1478, doi:10.3762/bjoc.8.166

• °C, silyl ketene acetal 7b in dichloromethane with c(3a-CF3CO2) = (1.7–2.5) × 10−5 M, kryptopyrrole 12a in acetonitrile with c(3a-CF3CO2) = 5.0 × 10−5 M). Comparison of calculated and experimental rate constants of electrophilic aromatic substitutions with iminium ions [56]. Aza-Michael additions of

Coupled chemo(enzymatic) reactions in continuous flow

• Ruslan Yuryev,
• Simon Strompen and
• Andreas Liese

Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169

• and solvent-free environment [38]. In the first noncatalyzed thermal aza-Michael addition performed at 80 °C, the racemic ester rac-46 is formed from cheap starting materials benzylamine (44) and trans-ethylcrotonate (45) (Scheme 14). Subsequently, Novozym 435 is applied for the kinetic resolution of

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• used. A proper choice of catalyst and reaction conditions is also needed to improve the efficiency of each reaction (Scheme 18) [18]. Consecutive one-pot transformations initiated by Heck reaction and terminated by intramolecular aza–Michael addition were developed by Hanson and coworkers to access a

• , and catalytic Pd2(dba)3·CHCl3 led to the production of the desired sultams 42 upon heating at 110 °C. A series of sultam derivatives of bioactive, related isoindol-1-one amides 43 were also prepared by entering acrylic acid into the Heck–aza–Michael process and coupling a second amine derivative

• sulfur dioxide. However, this Pd-catalyzed aminosulfonylation process proved inefficient with primary amines (Scheme 20) [20]. Multicomponent synthesis of nitrogen-containing heterocycles may also be initiated by an aza-Michael addition and terminated by a palladium-catalyzed ring-closure process [21

Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

• Václav Jurčík,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2011, 7, 759–766, doi:10.3762/bjoc.7.86

• explored as the enantiomerically pure amine. In the event 4a was generated after aza-Michael addition as a mixture of two stereoisomers, without any obvious diastereoisomeric bias (1:1, 0% de) as judged by both 1H and 19F NMR. β-Lactam ring closure, using thionyl chloride and triethylamine gave the N

• explored for the hydrogenolysis of 5a, however cleavage of the C–N bond proved very difficult and a satisfactory method could not be found. Therefore, (S)-α-(p-methoxyphenyl)ethylamine (3b) was explored as an alternative amine for the aza-Michael reaction, as removal of this amine using ceric ammonium

• nitrate (CAN) oxidation offered a milder deprotection method [15]. The aza-Michael reaction proved straightforward to generate 4b and then cyclisation again using thionyl chloride and triethylamine gave β-lactams 5b in a 40% de, presumably again a thermodynamically biased isomer ratio. The

Michael-type addition of azoles of broad-scale acidity to methyl acrylate

• Sławomir Boncel,
• Kinga Saletra,
• Barbara Hefczyc and
• Krzysztof Z. Walczak

Beilstein J. Org. Chem. 2011, 7, 173–178, doi:10.3762/bjoc.7.24

• reports on the synthesis of Michael-type adducts of azoles by the use of microwave irradiation [7][24]. The optimisation of aza-Michael reactions with N-methylimidazole as the base catalyst was published in 2007 by Liu et al [25]. However, when this catalyst was used with azoles of narrower-scale acidity

• important drugs, have seldomly been considered as aza-Michael donors due to their poor nucleophilicity and the possible tendency of adducts to undergo retro-Michael reactions [26]. Here, we present Michael-type addition of azoles, inter alia imidazole and 1,2,4-triazole derivatives of high acidity (pKa