Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• conversion because the neutralization can alter the aggregation states, producing a significant batch-to-batch variability. The direct insertion of magnesium metal into organic halides is the most common method used to prepare Grignard reagents but present difficulties: (1) sluggish reactions with ordinary

• often lower than of the corresponding zincates. The low solubility can clog the column or may reduce the insertion rate by forming a passivating layer over the metal particle surface. Few examples describe the production of organomagnesium species under flow conditions [36][37][38][39], and only three

• oxidative addition reactions is R–I > R–Br > R–Cl. To achieve the direct insertion of 2-chloropropane, the temperature was increased, and the best result was obtained at 80 °C, yielding iPrMgCl (0.78 M, 87%, Table S4, entry 7, Supporting Information File 1). Since iPrMgCl is more soluble in THF than the

Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions

• Xiaoming Ma,
• Suzhi Meng,
• Xiaofeng Zhang,
• Qiang Zhang,
• Shenghu Yan,
• Yue Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2020, 16, 1225–1233, doi:10.3762/bjoc.16.106

• oxidative addition of the Pd(0) species to alkene intermediate 8a leads to Pd-complex I. Intramolecular coordination of Pd-complex I with the C–C double bond forms complex II which is followed by the syn insertion of alkene to give complex III [50][51]. Subsequent β-hydride elimination of III gives complex

Palladium-catalyzed regio- and stereoselective synthesis of aryl and 3-indolyl-substituted 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones

• Valeria Nori,
• Antonio Arcadi,
• Armando Carlone,
• Fabio Marinelli and
• Marco Chiarini

Beilstein J. Org. Chem. 2020, 16, 1084–1091, doi:10.3762/bjoc.16.95

• mentioned (E)-vinylpalladium intermediate A (generated in situ from the insertion of a carbon–carbon triple bond in the initially formed arylpalladium complex) could also be involved in the aminopalladations with the alkynyltrifluoroacetanilides 5 through the formation of the π-complex B, followed by base

• process has been significantly extended to include σ-vinyl Pd(II) intermediates B obtained through oxidative addition/insertion of substrates 2 with Pd(0). This reaction efficiently led to challenging indoloquinolinones 6 through a sequential double cyclization. It is worth noting that, in both cases, the

• intramolecular alkyne insertion in the initially formed arylpalladium iodide A (leading to B) occured faster than the direct reaction of A with arylboronic acids or with 2-alkynyltrifluoroacetanilides. Experimental General methods Melting points are uncorrected. IR spectra were recorded with a Perkin Elmer

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• in equilibrium with a spectator bis-nitrene species 19 and proceeded through styrene 20 insertion, followed by ring closure and release of the aziridine. Interestingly, this otherwise classical mechanism is enabled by the accessibility of doublet and quadruplet states close in energy and this

• reminiscent of the entatic state model. The proposed mechanism (Scheme 12) involves the insertion of a nitrene or carbene group to the copper complex 22 to form intermediate 23. Subsequent alkene insertion yields species 25 and the group-transfer product (21a,h–j,n,o, 26a–g and 27a–o) is released upon ring

Aldehydes as powerful initiators for photochemical transformations

• Maria A. Theodoropoulou,
• Nikolaos F. Nikitas and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2020, 16, 833–857, doi:10.3762/bjoc.16.76

• presence of the nickel catalyst and a base via a typical oxidative addition, insertion, and reductive elimination sequence to afford the desired product (Scheme 29). In the absence of K2HPO4, only traces of the desired product were detected. Other known photosensitizers, such as acetone (4), acetophenone

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• ). This species serves as an active catalyst, nucleophilic at boron, via coordination with an alkene (307) which undergoes insertion to deliver the B–C bonded species via an intermediate that either undergoes elimination or reacts with an electrophile to form the product (e.g., 308, 309, Scheme 49) [92

• arylborylation of α-alkylstyrenes 387 has been investigated, delivering 1,1-adducts 389, 390 in the presence of palladacycle PCy3Pd G3, while 1,2-adducts 391–393 result using APhosPd G3. The former reaction proceeds through a second-stage β-hydride elimination/re-insertion pathway, although for the latter set of

• diborylated products 449–451; Scheme 71, top) [134]. The insertion of an in situ-formed Cu–B species into the aldehyde carbonyl was proposed, leading to the formation of a C–B bond. 1H NMR studies, however, did not confirm the formation of this Cu–O–C–B linkage 452. Instead, solely the Cu–C–O–B species 453

Rhodium-catalyzed reductive carbonylation of aryl iodides to arylaldehydes with syngas

• Zhenghui Liu,
• Peng Wang,
• Zhenzhong Yan,
• Suqing Chen,
• Dongkun Yu,
• Xinhui Zhao and
• Tiancheng Mu

Beilstein J. Org. Chem. 2020, 16, 645–656, doi:10.3762/bjoc.16.61

• reacts with PPh3 to form RhCl(PPh3)3, which is able to activate C–I bonds in aryl iodides realizing the insertion of CO and hydrogenolysis with H2. The final trapping of HI by the base Et3N regenerates the catalyst to complete the reaction cycle. As far as we know, this is the first time that

• ]. First, RhCl3·3H2O reacted with PPh3 to form Rh(PPh3)3Cl (A), followed by an oxidative addition of Rh(PPh3)3Cl (A) to the aryl iodide, producing the corresponding arylrhodium complex (B). Then, the coordination and insertion of CO led to the formation of benzoylrhodium complex (C). Next, metathesis with

• reacted via a redox reaction to form Rh(PPh3)3Cl, which is the active catalytic species able to activate C–I bonds in the aryl iodides for the insertion of CO in the next step. The base Et3N neutralized the proton in the intermediate rhodium hydroiodide (D) complex and regenerated the active Rh species

Preparation and in situ use of unstable N-alkyl α-diazo-γ-butyrolactams in Rh^II-catalyzed X–H insertion reactions

• Maria Eremeyeva,
• Daniil Zhukovsky,
• Dmitry Dar’in and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2020, 16, 607–610, doi:10.3762/bjoc.16.55

• found to be unstable and to undergo unproductive dimerization to bishydrazones, were successfully converted immediately to various X–H insertion products with alcohols, aromatic amines and thiols via an in situ RhII-catalyzed reaction. With aliphatic amines or unreactive, sterically hindered anilines

• , the reactions tended to yield enamine adducts. Keywords: in situ reactions; N-alkyl 2-pyrrolidones; RhII-catalyzed insertion reactions; stability of diazo compounds; Introduction Recently, we described the first synthesis and subsequent transformations of a rare type of cyclic α-diazocarbonyl

• compounds, namely, α-diazo-γ-butyrolactams [1]. In particular, N-aryl-α-diazo-γ-butyrolactams 1 were efficiently transformed into pyrrolinones 2 upon the treatment with AgOTf (1 mol %) and into α-alkoxy derivatives 3 via Rh2(OAc)4-catalyzed O–H insertion reactions with various alcohols. In contrast, N-alkyl

A combinatorial approach to improving the performance of azoarene photoswitches

• Joaquin Calbo,
• Aditya R. Thawani,
• Rosina S. L. Gibson,
• Andrew J. P. White and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2019, 15, 2753–2764, doi:10.3762/bjoc.15.266

• scaffold, the theoretical calculations at the PBE0-D3/6-31G** level indicate that an insertion of electron-poor fluorine atoms in the ortho-position of the aryl ring (4pzH-F1 and 4pzH-F2) leads to an increase in the half-life from ca. 1000 days in 4pzH to 2000 days in 4pzH-F1 and to 4000 days in 4pzH-F2

• above, theoretical calculations indicate that the addition of ortho-fluoro atoms leads to higher Z-isomer stability, whereas the opposite effect is found upon chlorine ortho-substitution (Table 1). The insertion of one and two electron-donating OMe and Pyr groups systematically improve the Z-isomer

• -lives upon ortho-F substitution. In sharp contrast, the insertion of bulkier chlorine atoms at the ortho position(s) induces destabilizing steric clashes, as well as negligible electrostatic forces (chlorine atomic charge of +0.04e; Figure S8 in Supporting Information File 1). Somewhat similar to the

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• subsequent migratory insertion furnishes the seven-membered metallacycle D. Finally, reductive elimination leads to compounds 4a and the concomitant reoxidation of Rh(I) to Rh(III) by the Cu(II) salt completes the catalytic cycle. Conclusion In conclusion, we have developed a versatile method for the

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• substrates was reported by Yu and co-workers (Scheme 13) [50]. Enantioenriched benzyl fluorides were obtained by aid of a chiral α-amino amide transient directing group (TDG). Notably, the condensation of this bulky amino amide with the aldehyde led to control of the stereochemistry of the C–H insertion step

Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

• Sara Peeters,
• Linn Neerbye Berntsen,
• Pål Rongved and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2019, 15, 2156–2160, doi:10.3762/bjoc.15.212

• decomposition of diazo compounds, are particularly versatile intermediates in organic synthesis, as they partake in cyclopropanation and C–H insertion reactions with high levels of selectivity [2]. This transition-metal-catalyzed carbene transfer has emerged as a mild and attractive route to indole

• carbene transfer reaction typically give N–H, C–H (at C3) and double N–H/C–H insertion products. The presence of electron-withdrawing groups on the indole nitrogen makes it possible to cyclopropanate the indole C2–C3 double bond and isolate indoline cyclopropanes. We recently discovered that Rh carbenes

• . These halo-acceptor carbenoids undergo cyclopropanation of N–H indoles with high selectivity, and only traces of C–H or N–H insertion products were observed. The yield of ethyl quinoline-3-carboxylate is dependent on the halogen in X-EDA (Cl: 90%, Br: 84%, I: 70%). The reaction works well for

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

• 2-AP to Cu(OTf)2, forming an intermediate 7, that was followed by migratory insertion by haloalkyne (Scheme 4). The organocopper species 8 thus formed would undergo deprotonation/oxidation and finally reductive elimination to give the cyclized product 6 (Scheme 4). Along with the unprecedented

• Suzuki, Sonogashira and Heck coupling reactions (Scheme 48). The reaction proceeded by the formation of 1-iodoalkyne 142 which was characterized by mass and 1H NMR spetra. This iodoalkyne then formed a complex of Cu(I) with 2-AP. This was followed by migratory insertion of haloalkyne to form reactive Cu

Introduction of an isoxazoline unit to the β-position of porphyrin via regioselective 1,3-dipolar cycloaddition reaction

• Xiujun Liu,
• Xiang Ma and
• Yaqing Feng

Beilstein J. Org. Chem. 2019, 15, 1434–1440, doi:10.3762/bjoc.15.143

• Vilsmeier reaction was carried out after insertion of Cu2+ into the cavity of TPP. In the presence of concentrated H2SO4 the Cu2+ was removed to give the 2-formyl derivative TPP-CHO. Subsequently, the formyl group was reduced by NaBH4, accompanied with chlorination by SOCl2, to afford the chloromethyl

• the β-position, a Wittig reaction was performed, in which the porphyrin phosphonium salt 1 reacted with 4-MeCO2-benzaldehyde in the presence of DBU to furnish the double bond, followed by insertion of Zn ions into the porphyrin cavity to give compound 2. Nitrile oxides [45] as one of the most reactive

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

• Alexander N. Reznikov,
• Anastasiya E. Sibiryakova,
• Marat R. Baimuratov,
• Eugene V. Golovin,
• Victor B. Rybakov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2019, 15, 1289–1297, doi:10.3762/bjoc.15.127

• , which allows to obtain chiral cyclic sulfones with high enantioselectivity [10][11][12]. Also non-racemic cyclic sulfones can be obtained by the Diels–Alder reaction, catalyzed by chiral Lewis acids or organocatalysts. Rh- and Cu-catalyzed CH-insertion reactions occurring at moderate or high

Insertion of [1.1.1]propellane into aromatic disulfides

• Robin M. Bär,
• Gregor Heinrich,
• Martin Nieger,
• Olaf Fuhr and
• Stefan Bräse

Beilstein J. Org. Chem. 2019, 15, 1172–1180, doi:10.3762/bjoc.15.114

• as bioisosters of para-substituted benzene and alkyne moieties. The most promising precursor for BCPs is [1.1.1]propellane (1). The available methods to synthesize BCPs are quite limited and many groups contribute to the development of novel methods. The insertion of 1 into disulfide bonds is known

• of the thiol addition [24]. In analogy to this reaction, the insertion of 1 into disulfide bonds has been discovered early, but only very few examples can be found in the literature [10][11][25][26][27][28]. In this work, the insertion of [1.1.1]propellane (1) into disulfide bonds was investigated

• the first to use UV irradiation in this reaction, but did not report detailed conditions [28]. They used diacetyldithiol and 1 to obtain bisacetylthio[n]staffanes. To find feasible conditions for the insertion of 1 into disulfide bonds, a screening with irradiations of different wavelengths and other

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

• experiments allowed the authors to propose the mechanism as follows (Scheme 20). First, cyclocondensation of 2-aminobenzamide (59) with 2-bromobenzaldehyde (62) to form intermediate 63 is followed by oxidative addition of Pd(0) to provide palladium complex 64. Then, insertion of CO (23) in the C–Pd bond

• 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

Synthesis of functionalized diazocines for application as building blocks in photo- and mechanoresponsive materials

• Widukind Moormann,
• Daniel Langbehn and
• Rainer Herges

Beilstein J. Org. Chem. 2019, 15, 727–732, doi:10.3762/bjoc.15.68

• photostationary states (PSS (385 nm): 25–30% trans). The electronic decoupling of the azobenzene unit and the oxygen and nitrogen containing functional groups (OH, OR, N3, NH2) was achieved by insertion of one or two CH2 groups. Thereby, the switching efficiencies were increased by about a factor of two (PSS (385

Design, synthesis and spectroscopic properties of crown ether-capped dibenzotetraaza[14]annulenes

• Krzysztof M. Zwoliński and
• Julita Eilmes

Beilstein J. Org. Chem. 2019, 15, 617–622, doi:10.3762/bjoc.15.57

• differentiated Lewis-basic binding sites, however, from a broader perspective, the nature of the DBTAA binding site can be easily switched into a Lewis-acidic one after appropriate metal insertion (e.g., with zinc(II) ions) [33]. The crown-capped DBTAA’s were synthesized by refluxing 1,4,10-trioxa-7,13

Intramolecular cascade annulation triggered by rhodium(III)-catalyzed sequential C(sp²)–H activation and C(sp³)–H amination

• Liangliang Song,
• Guilong Tian,
• Johan Van der Eycken and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 571–576, doi:10.3762/bjoc.15.52

• intramolecular migratory insertion affords intermediate C. Reductive elimination and subsequent oxidative addition give intermediate D. Then two pathways are involved in the following steps. In the main pathway (path a), intermediate D undergoes β-H elimination and tandem cyclization to give product 3a and Rh–H

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• -pot procedure with one purification step), much better yields, no need of expensive catalysts as in ring-closing metathesis (RCM) reaction and higher complexity/diversity on the macrocyclic ring, e.g., insertion of heteroatoms that could improve the ADMET properties (Scheme 1) [4]. Results and

Synthesis of C₃-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step

• Sambasivarao Kotha and
• Saidulu Todeti

Beilstein J. Org. Chem. 2019, 15, 371–377, doi:10.3762/bjoc.15.33

• . Results and Discussion The required zinc insertion compound 7 was prepared from L-serine (3). Thus, commercially available L-serine (3) was treated with acetyl chloride in methanol to give methyl ester 4, which was subjected to N-Boc protection with di-tert-butyl dicarbonate (Boc2O) and triethylamine in

• iodo compound 6 was treated with freshly activated Zn in DMF at room temperature to afford the zinc insertion product 7 (Scheme 1) [43]. With the organozinc compound 7 at hand we turned to the synthesis of the halide component for the attempted Negishi coupling. For this 4-iodoacetophenone (8) was

• of Zn insertion reaction, stirring was stopped and the solid was allowed to settle down. The supernatant was carefully transferred to a suspension of triiodo derivative 9 (500 mg, 0.73 mmol) in DMF (10 mL) at room temperature. Five mol % tetrakis(triphenylphosphane)palladium (Pd(PPh3)4) was added to

A novel and efficient synthesis of phenanthrene derivatives via palladium/norbornadiene-catalyzed domino one-pot reaction

• Yue Zhong,
• Wen-Yu Wu,
• Shao-Peng Yu,
• Tian-Yuan Fan,
• Hai-Tao Yu,
• Nian-Guang Li,
• Zhi-Hao Shi,
• Yu-Ping Tang and
• Jin-Ao Duan

Beilstein J. Org. Chem. 2019, 15, 291–298, doi:10.3762/bjoc.15.26

• is presented in Scheme 5. As is commonly considered, the aryl-PdII complex A is formed by oxidative addition of aryl iodide to the Pd0 complex, which is followed by the insertion of norbornadiene to the C–Pd bond of A to produce B. Then, an ortho-C–H activation reaction occurs to B, which offers

Oxidative radical ring-opening/cyclization of cyclopropane derivatives

• Yu Liu,
• Qiao-Lin Wang,
• Zan Chen,
• Cong-Shan Zhou,
• Bi-Quan Xiong,
• Pan-Liang Zhang,
• Chang-An Yang and
• Quan Zhou

Beilstein J. Org. Chem. 2019, 15, 256–278, doi:10.3762/bjoc.15.23

• intermediate 15, which undergoes a ring-opening process to form the radical intermediate 16 [52][53]. Then, the radical 16 reacts with copper(II) acetate to produce organocopper intermediate 17. Finally, the intramolecular insertion of C–Cu in compounds 17 to the carbon–carbon double bond takes place to

Olefin metathesis in multiblock copolymer synthesis

• Maria L. Gringolts,
• Yulia I. Denisova,
• Eugene Sh. Finkelshtein and
• Yaroslav V. Kudryavtsev

Beilstein J. Org. Chem. 2019, 15, 218–235, doi:10.3762/bjoc.15.21

• the initiator efficiency. The sacrificial approach also helps to describe the multiblock copolymer structure: owing to the acid-labile acetal group, polymer scission takes place at the point of the dioxepin insertion thus providing an indirect way to detect the monomer location [73]. Supramolecular