Additive-controlled chemoselective inter-/intramolecular hydroamination via electrochemical PCET process

• Kazuhiro Okamoto,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2024, 20, 264–271, doi:10.3762/bjoc.20.27

• , entry 3); thus, the phosphate base plays a crucial role in N-alkylation, while its basicity is insufficient to promote aza-Michael addition (pKa of the conjugate acid of the phosphate base is 1.72 in H2O) [12]. Furthermore, N-alkylation proceeded in a divided cell (anodic chamber); thus, the possibility

A novel recyclable organocatalyst for the gram-scale enantioselective synthesis of (S)-baclofen

• Gyula Dargó,
• Dóra Erdélyi,
• Balázs Molnár,
• Péter Kisszékelyi,
• Zsófia Garádi and
• József Kupai

Beilstein J. Org. Chem. 2023, 19, 1811–1824, doi:10.3762/bjoc.19.133

• (Figure 1). Results and Discussion Synthesis of the lipophilic cinchona squaramide organocatalyst Previously, we successfully applied quinine-derived squaramide (SQ) organocatalyst 1 in stereoselective Michael and aza-Michael additions with excellent enantiomeric excess values [26]. Our aim was to recycle

Synthesis of 7-azabicyclo[4.3.1]decane ring systems from tricarbonyl(tropone)iron via intramolecular Heck reactions

• Aaron H. Shoemaker,
• Elizabeth A. Foker,
• Elena P. Uttaro,
• Sarah K. Beitel and
• Daniel R. Griffith

Beilstein J. Org. Chem. 2023, 19, 1615–1619, doi:10.3762/bjoc.19.118

• number of alkaloid natural products can be accessed from commercially available tropone in as little as five steps: 1) formation of tricarbonyl(tropone)iron, 2) aza-Michael addition, 3) amine protection, 4) photodemetallation, and 5) intramolecular Heck reaction (two steps – aza-Michael addition and

Metal catalyst-free N-allylation/alkylation of imidazole and benzimidazole with Morita–Baylis–Hillman (MBH) alcohols and acetates

• Olfa Mhasni,
• Jalloul Bouajila and
• Farhat Rezgui

Beilstein J. Org. Chem. 2023, 19, 1251–1258, doi:10.3762/bjoc.19.93

• reflux with an azeotropic distillation, was successfully carried out with no catalysts or additives, affording the corresponding N-substituted imidazole derivatives in good yields. On the other hand, in refluxing toluene or methanol, the aza-Michael addition of imidazole onto acyclic MBH alcohols was

• performed using DABCO as an additive, leading to the corresponding 1,4-adducts in 70–84% yields. Keywords: allylic substitution; aza-Michael addition; imidazole; Morita–Baylis–Hillman; Introduction Morita–Baylis–Hillman (MBH) adducts are multifunctionalized compounds having both a hydroxy moiety and a

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• of the Boc-protecting group with the Teoc group then gave phenol 136. Compound 136 was then subjected to a highly diastereoselective oxidative phenolic coupling giving fused tetracyclic architecture 137. Follow-up acid-mediated intramolecular aza-Michael addition and subsequent alkene reduction

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• 1-substituted 2-ethoxy-1,2-azaphospholidine-4-carboxylate 2-oxides 203 were synthesized in 70% and 39% yields, respectively, from ethyl 2-((chloro(ethoxy)phosphoryl)methyl)acrylate (202) and benzyl- and adamantylmethylamines via aza-Michael addition and intramolecular nucleophilic substitution. The

• synthetic method showed very limited substrate scope. Only less bulky primary amines underwent the first aza-Michael addition and then intramolecular nucleophilic substitution. However, aromatic amines, aniline, 2,3-dihydro-1H-inden-4-amine, and the bulky aliphatic primary amine adamantylamine did not

• -phenylphosphonamidates 240a (R’ = OEt) and diaryl-N-phenylphosphinamides 240b–d (R’ = Ar), respectively, with methyl acrylate (241) via the rhodium-catalyzed oxidative coupling and subsequent intramolecular aza-Michael addition. Methyl acrylate (241) could be replaced by various electron-deficient olefins 244, including

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• assigned as 1-alkyl-3,5,5-trimethyl-5,6-dihydro-1H-azepino[4,3,2-cd]indoles 8. The authors proposed that aza-Michael addition of 4-aminoindoles 7 to in situ generated mesityl oxide gives compound 9 which undergoes a regioselective intramolecular cyclization–dehydration sequence to furnish 8. In 2019, Zou

• [4,3,2-cd]indoles via indole C3 regioselective aza-Michael addition/cyclization/dehydration sequence. Indole C3 regioselective Pictet−Spengler reaction of 2-(1H-indol-4-yl)ethanamines. Indole C3 regioselective hydroindolation of cis-β-(α′,α′-dimethyl)-4′-methindolylstyrenes. Indole C3 regioselective

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• by a review article devoted to aza-Michael reactions of amines and amides [17]. The evolution of the understanding of noncovalent activation modes led to the realization that anion-binding is a critical feature in many transformations. Halide anions are highly relevant and widely occurring within

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• racemic codonopsinol B (1) and its N-nor-methyl analogue 2 starting from achiral materials. Four consecutive stereocenters in the target molecules were accomplished sequentially by the organocatalytic aza-Michael addition of N-Cbz-protected hydroxylamine to (E)-4-methoxycinnamaldehyde, the trans

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• asymmetric aza-Michael reaction (aza-MR) alone or in tandem with other organic reaction(s) is an important synthetic tool to form new C–N bond(s) leading to developing new libraries of diverse types of bioactive nitrogen compounds. The synthesis and application of a variety of organocatalysts for

• organocatalysts in asymmetric aza-MR. Keywords: asymmetric aza-Michael reaction; covalent bonding catalysis; nitrogen heterocycles; non-covalent bonding catalysis; organocatalysis; Introduction The Michael reaction though discovered about 135 years ago [1][2] continues to attract attention of the chemists owing

• to its potential of making a vast variety of organic compounds particularly of pharmacological importance accessible. Over the years, its many versions known as aza-Michael, thio-Michael, oxa-Michael, phospha-Michael, etc. have been developed and well exploited for their synthetic applications [3][4

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• yield. Aliphatic amines were also tolerated, providing the desired products in only moderate yield. The plausible mechanism involves a tandem base-promoted aza-Michael addition, 1,2-iodocyclization, and iodine-mediated oxidative aromatization. In 2017, Zhang and co-workers reported a silver-catalyzed

• standard conditions. The proposed catalytic cycle included aza-Michael addition of arylamines, Lewis acid copper(II)-catalyzed intramolecular 5-endo-dig cyclization, protonation, and oxidation to provide the final products, tetrasubstituted pyrroles 39. The introduction of a trifluoromethyl group into

Electron-rich triarylphosphines as nucleophilic catalysts for oxa-Michael reactions

• Susanne M. Fischer,
• Simon Renner,
• A. Daniel Boese and
• Christian Slugovc

Beilstein J. Org. Chem. 2021, 17, 1689–1697, doi:10.3762/bjoc.17.117

• ) after 24 h. To illustrate that the reaction does not stop after 24 h the conversions were re-checked after 21 d. After this time with TMTPP as the catalyst, conversions of 44% (3a), 92% (3b), 98% (3c), and 91% (3d) are obtained. No indications for aza-Michael reactions potentially leading to polyamide 3

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• cascade aza-Michael addition/olefin hydroalkylation reaction between N-tosylallylamines and α,β-unsaturated ketones using a catalytic system of a gold(I) complex and a silver salt [45]. The spiro compound 25, which was obtained in moderate yield and with poor diastereoselectivity after a 20 h reaction

• , was the only example reported of a quaternary carbon center synthesis (Scheme 12). The observations that no reaction was detected in the absence of AgOCl and that only an aza-Michael adduct was observed in the absence of the gold(I) complex led the authors to propose that the silver(I) salt promoted

• the aza-Michael addition and that only the cationic gold(I) complex was associated with the intramolecular hydroalkylation reaction. These observations justified the use of a three-fold excess of AgOCl in relation to the gold complex since the silver salt participated both as a source of a non

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• Zentralblatt summary. Additionally, ambiguities exist on the molecularity of the various reactions since Guareschi was often preparing β-aminocarbonyl derivatives in situ from the self-condensation of acetone and the aza-Michael trapping of mesityl oxide. This method works well only for acetone, while further

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• -workers found that combining an asymmetric nucleophilic addition to the chiral imine, with an intramolecular conjugate aza-Michael reaction, the expected 1,3-disubstituted isoindolines were produced with high diastereoselectivity [96]. Importantly, depending on the base involved in the intramolecular aza

• -Michael reaction, it was possible to reach either cis- or trans-isoindolines, 69 and 70, respectively, from the same precursor 68. The authors proposed that the thermodynamically more stable cis-isomer 69 is formed when TBAF was used. Meanwhile, working under kinetic conditions (DBU as base), trans-isomer

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• utilizing electron-poor alkenes as the reaction partners that would undergo aza-Michael addition reactions on the Cbz-carbamates (Scheme 4). Driven by the desire to develop readily scalable routes towards the target products 8, continuous flow processing was again exploited. In a first approach the use of

• -based aza-Michael addition reactions. This novel approach allows for the creation of important chemical building blocks whilst demonstrating a new use of biocatalysts in continuous flow processes. Scope of Cbz-carbamate products obtained via flow process (*tRes = 60 min, **T = 80 °C; isolated yields

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• organic processes and have attracted considerable interest in this regard. Ru has efficiently catalyzed C–H activation reactions for C–C bond formation, aza-Michael reactions and many more MCRs [27][76][77]. During the writing of this review, we came through the fact that ruthenium catalysts were mostly

• -benzenedicarboxylate), Puthiaraj and co-workers have unprecedently discovered the catalytic activity of this metal-organic framework (MOF) for the synthesis of imidazo[1,2-a]pyridines [100]. The three-component, one-pot reaction between 1, 3 and nitromethane (10, Scheme 5) involved an intermolecular aza-Michael

• addition with a subsequent intramolecular cyclization catalyzed by Cu(BDC)MOF. Further, the LC–MS study of the reaction mixture has shown the imine formation to be the major pathway rather than β-nitrostyrene. The reaction involved a two-step reaction mechanism in which aza-Michael adduct 13 was formed in

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