Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• reported herein different methods for their synthesis. 1.1. Negishi cross coupling of aryl halide and organozinc compounds Jackson and co-workers reported the synthesis of a range of phenylalanine derivatives via Negishi cross-coupling reactions of aryl halides and Zn homoenolates of the protected (R

• )-iodoalanine 2. The reaction was activated using Pd(0) as a catalyst. A palladium-catalyzed cross-coupling reaction between an organozinc iodide and aryl halides offers a convenient method for the direct preparation of protected fluorinated Phe analogues 3. Thus, cross coupling of the protected iodoalanine 2

• with 4-fluorobromobenzene (1a) or 2- and 4-fluoroiodobenzene (1b and 1c), respectively, was accomplished using the reported coupling conditions in Scheme 1 to give the N-Boc-protected 2- or 4-fluoro-ʟ-phenylalanine esters 3a,b [34][35]. On the other hand, attempted cross-coupling of fluoroiodobenzenes

Suzuki–Miyaura cross coupling is not an informative reaction to demonstrate the performance of new solvents

• James Sherwood

Beilstein J. Org. Chem. 2020, 16, 1001–1005, doi:10.3762/bjoc.16.89

• coupling is often unaffected by the choice of solvent, and therefore the Suzuki–Miyaura reaction provides limited information regarding the usefulness of any particular solvent for organic synthesis. Keywords: cross coupling; green solvents; palladium; solvent selection; Suzuki reaction; Findings The

• , equilibria, solubility, and ultimately product yield. If there is an observable change in reaction performance correlating to one or more solvent properties (often polarity), then it is possible to identify and implement an optimum solvent. Suzuki–Miyaura cross coupling is the premier method of palladium

• applicable) of Suzuki–Miyaura cross couplings [8]. Despite this, the reaction is generally tolerant of a wide range of solvents (often an ether or amide solvent is used, and water is a common co-solvent). This calls into question the benefits of using Suzuki–Miyaura cross coupling as a test of new solvents

Aryl-substituted acridanes as hosts for TADF-based OLEDs

• Naveen Masimukku,
• Dalius Gudeika,
• Oleksandr Bezvikonnyi,
• Ihor Syvorotka,
• Rasa Keruckiene,
• Dmytro Volyniuk and
• Juozas V. Grazulevicius

Beilstein J. Org. Chem. 2020, 16, 989–1000, doi:10.3762/bjoc.16.88

• according to the reported procedure [28]. The subsequent alkylation of 1 using bromoethane afforded the N-ethylated dibromo compound 2 in 80% yield. The target compounds 3–6 were then obtained by Suzuki cross-coupling reactions between brominated acridan 2 and the respective phenylboronic acids in the

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis

• Quentin Lefebvre,
• Christophe Salomé and
• Thomas C. Fessard

Beilstein J. Org. Chem. 2020, 16, 982–988, doi:10.3762/bjoc.16.87

• collections. These are of high value to medicinal chemists to provide defined exit vectors and facilitate rational lead evolution [2][3][4][5][6][7]. Thus, we were interested in developing reliable synthetic methods and technologies to apply metal-catalyzed cross-coupling reactions to such scaffolds, which

• -catalyzed cross-coupling reactions [9]. Recently, milder cross-coupling methods using more abundant and affordable metals such as nickel, in combination with photochemistry or electrochemistry, significantly improved accessibility to N-arylated complex amines [10][11][12]. Results and Discussion As we

• initiated a high-throughput program of fragment-based library generation and after shortcomings using more classical cross-coupling conditions, we turned our attention to the photoredox-nickel dual-catalysis strategy recently reported by MacMillan and Buchwald [10]. The reported conditions use lower

Synthesis and properties of tetrathiafulvalenes bearing 6-aryl-1,4-dithiafulvenes

• Aya Yoshimura,
• Hitoshi Kimura,
• Kohei Kagawa,
• Mayuka Yoshioka,
• Toshiki Itou,
• Dhananjayan Vasu,
• Takashi Shirahata,
• Hideki Yorimitsu and
• Yohji Misaki

Beilstein J. Org. Chem. 2020, 16, 974–981, doi:10.3762/bjoc.16.86

• decomposed at around 41–42 °C (Scheme 1a). Therefore, we achieved the synthesis of 3a by Pd-catalyzed thienylation of TTF using acetal-protected 8, followed by deprotection using PTSA·H2O and P(OEt)3-mediated cross coupling with 11 (Scheme 1b). The cross-conjugated molecule 4 was prepared in two procedures

• ; one was the palladium-catalyzed C–H arylation of TTF with bromide 12 (Scheme 2a) and the other was the Vilsmeier–Haack reaction of 1a, followed by triethyl phosphite-mediated cross coupling with 11 (Scheme 2b). Theoretical calculations The DFT calculations of compounds 1a, 3a, and 4 have been carried

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

• use of copper(I) complexes bearing redox-active guanidine ligands 12 for catalytic aerobic homo- and cross-coupling of phenols with dioxygen as oxidation source (Scheme 9). This strategy allowed access to nonsymmetrical biphenols and the best results were obtained with dinuclear complex 13

• selectivity. Homo- and cross-coupling adducts 16a and 16b–g were obtained from the corresponding phenols (14a–e and 15a–c) as shown in the bottom of Scheme 9 with high chemoselectivity. C–N bond formation While copper complexes are at the heart of oxidative biological networks, the introduction of nitrogen is

One-pot synthesis of dicyclopenta-fused peropyrene via a fourfold alkyne annulation

• Ji Ma,
• Yubin Fu,
• Junzhi Liu and
• Xinliang Feng

Beilstein J. Org. Chem. 2020, 16, 791–797, doi:10.3762/bjoc.16.72

• and Discussion The synthesis of compound 1 is depicted in Scheme 2. Firstly, 2,7-bis(Bpin)pyrene (3) was prepared using an iridium-catalyzed borylation of pyrene (67% yield). Then, 2,7-diphenylpyrene (4) was obtained by Suzuki cross-coupling of 3 and bromobenzene in 77% yield. After that, the

Towards triptycene functionalization and triptycene-linked porphyrin arrays

• Gemma M. Locke,
• Keith J. Flanagan and
• Mathias O. Senge

Beilstein J. Org. Chem. 2020, 16, 763–777, doi:10.3762/bjoc.16.70

• investigated for its use as a rigid isolating unit in the synthesis of multichromophoric arrays. Sonogashira cross-coupling conditions are utilized to attach various porphyrins and boron dipyrromethenes (BODIPYs) to the triptycene scaffold. While there are previous examples of triptycene porphyrin complexes

• evident linearity in these systems. Moreover, initial UV–vis and fluorescence studies show the promise of triptycene as a linker for electron transfer studies, showcasing its isolating nature. Keywords: BODIPY; Pd-catalyzed cross-coupling; porphyrins; Sonogashira cross-coupling; triptycene; Introduction

• complexes such as 2 were synthesized by us with the purpose of conducting electron transfer studies [25]. Both Suzuki and Sonogashira cross-coupling reactions were employed to realize this new class of triptycene-linked trimeric porphyrins. The three porphyrins, or three BODIPYs in 2 were either linked

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• to build the desired 1,3-dienic units. The advantageous association of this approach with name reactions like Grignard, Wittig, Diels–Alder, Suzuki–Miyaura, Heck cross-coupling, etc. is illustrated. Examples unveil the generality of such tandem reactions in providing not only the intricate structures

• other memory impairments, namely (−)-galanthamine (13), has attracted great interest for its structural complexity and specific bioactivity. The total synthesis of compound 13, described by Brown et al. [81], involved an enyne ring-closing metathesis and a Heck cross-coupling as the key reactions for

• catalyst (3 mol %) to give the corresponding 1,3-diene intermediate in 85% yield (Scheme 16). The subsequent hydroboration and oxidation to homoallylic alcohol, followed by a palladium-catalyzed Heck cross-coupling, an allylic oxidation with SeO2, mesylation, and deprotection, afforded (−)-galanthamine (13

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

• incorporating silicon or boron into new or existing drugs, in addition to their use as building blocks in cross-coupling reactions en route to various targets of both natural and unnatural origins. In this review, recent protocols relying on copper-catalyzed sp3 carbon–silicon and carbon–boron bond-forming

• ] are common partners in a variety of important cross-coupling reactions. They are also especially valuable precursors to other functional groups such as organic halides, alcohols [5][6][7], etc. Moreover, recent drug discovery efforts have shifted towards the incorporation of these non-natural

• conditions, a rare cross-coupling takes place (Scheme 62) [115]. The cooperative effect of a catalytic system consisting of Cu/Ni (e.g., Ni(acac)2, CuCl, and PCy3) was also reported by Nakao et al. leading to regio- and stereoselective arylboration of 1-arylalkenes with aryl chlorides or tosylates. The

Towards the total synthesis of chondrochloren A: synthesis of the (Z)-enamide fragment

• Jan Geldsetzer and
• Markus Kalesse

Beilstein J. Org. Chem. 2020, 16, 670–673, doi:10.3762/bjoc.16.64

• obtained through a seven-step sequence starting from ᴅ-ribonic acid-1,4-lactone. The (Z)-vinyl bromide 4 is accessible in four steps from 4-hydroxybenzaldehyde. The pivotal cross coupling between both fragments was achieved after extensive experimentation with copper(I) iodide, K2CO3 and N,N

• ′-dimethylethane-1,2-diamine. Keywords: cross coupling; myxobacteria; natural product; ribolactone; Z-enamide; Introduction In the course of our program to provide synthetic access to biologically active natural products we targeted complex polyketides and depsipetides [1][2][3][4][5][6][7][8][9][10]. One

• investigations on the construction of the segments 3 and 4 as well as our results on the cross coupling between both fragments. Our retrosynthetic approach (Figure 1) divides chondrochloren A (1) into three fragments of similar complexity: amide 2, (Z)-bromide 4 and amide 3. For the coupling of amide 3 and (Z

Direct borylation of terrylene and quaterrylene

• Haruka Kano,
• Keiji Uehara,
• Kyohei Matsuo,
• Hironobu Hayashi,
• Hiroko Yamada and
• Naoki Aratani

Beilstein J. Org. Chem. 2020, 16, 621–627, doi:10.3762/bjoc.16.58

• hinderance of Bpin moieties. Finally, to demonstrate the utility of the borylated oligorylenes, the Suzuki–Miyaura cross-coupling reaction of TB4 under the standard conditions was performed (Scheme 3). Coupling of TB4 and 2-bromomesitylene with Pd(PPh3)4, Cs2CO3 and CsF in a mixture of toluene/DMF furnished

• an Ir-catalyzed borylation reaction. Our results provide a highly potential route to various functional oligorylene derivatives. In fact, TB4 could be transformed into the tetraarylterrylene TM4 in good yield by the conventional cross-coupling reaction. TB4 exhibits face-to-face interaction in the

• -dioxaborolan-2-yl. Synthesis of 2,5,12,15-tetrakis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quaterrylene (QB4): (a) (Bpin)2 (12 equiv), [Ir(OMe)cod]2 (20 mol %), di-tert-butylbipyridyl (40 mol %), 1,4-dioxane, at 105 °C, 38 h, yield 0.4%. Suzuki–Miyaura cross-coupling reaction of TB4 with 2-bromomesitylene

Regioselectively α- and β-alkynylated BODIPY dyes via gold(I)-catalyzed direct C–H functionalization and their photophysical properties

• Takahide Shimada,
• Shigeki Mori,
• Masatoshi Ishida and
• Hiroyuki Furuta

Beilstein J. Org. Chem. 2020, 16, 587–595, doi:10.3762/bjoc.16.53

• ], and borylation [32]), has been in great demand recently rather than the conventional multistep synthesis with nucleophilic substitution/cross-coupling via halogenation of BODIPYs [33] or from the activated precursors [34] via unstable pyrrolic intermediates. In particular, halogenation (e.g

• Glaser-coupling reactions [37]. Conventionally, an alkynylation of the BODIPY core has been achieved by palladium-catalyzed Sonogashira cross-coupling with halogenated BODIPYs (Figure 1b) [35][37]. However, due to the coexistence of multiple C–H bonds, a regioselective direct C–H alkynylation of the

Efficient synthesis of 3,6,13,16-tetrasubstituted-tetrabenzo[a,d,j,m]coronenes by selective C–H/C–O arylations of anthraquinone derivatives

• Seiya Terai,
• Yuki Sato,
• Takuya Kochi and
• Fumitoshi Kakiuchi

Beilstein J. Org. Chem. 2020, 16, 544–550, doi:10.3762/bjoc.16.51

• groups to form biaryl frameworks. Traditionally, transition-metal-catalyzed cross-coupling reactions of aryl halides or pseudohalides with arylmetal reagents have been employed for the connection of two aryl units [5][6][7][8][9]. However, in search of more efficient synthetic routes, C–H arylation

• reaction, followed by dehydrogenative photocyclization, and FeCl3-mediated oxidative cyclization (Scheme 2a) [43]. Tao, Chao, and co-workers succeeded in the preparation of similar tetrasubstituted tetrabenzocoronenes by a Corey–Fuchs reaction, followed by a Suzuki–Miyaura cross-coupling, and a two-step

Copper-catalyzed remote C–H arylation of polycyclic aromatic hydrocarbons (PAHs)

• Anping Luo,
• Min Zhang,
• Zhangyi Fu,
• Jingbo Lan,
• Di Wu and
• Jingsong You

Beilstein J. Org. Chem. 2020, 16, 530–536, doi:10.3762/bjoc.16.49

• molecules, thus having drawn much attention. Transition metal-catalyzed C–X/C–M cross-coupling reactions such as Suzuki and Stille couplings are the main approaches to achieve the arylation of PAHs [7][8][9][10][11]. However, the selective arylation of the C7-position of 1-naphthoic acid derivatives remains

Synthesis of triphenylene-fused phosphole oxides via C–H functionalizations

• Md. Shafiqur Rahman and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2020, 16, 524–529, doi:10.3762/bjoc.16.48

• phosphole oxides through C–H functionalization and cross-coupling reactions. The phosphole ring was constructed in the early stage of the synthesis by a three-component assembly method featuring a 1,4-cobalt migration as the key step. Unlike other C–H activation/alkyne annulation approaches to benzo[b

Controlling alkyne reactivity by means of a copper-catalyzed radical reaction system for the synthesis of functionalized quaternary carbons

• Goki Hirata,
• Yu Yamane,
• Naoya Tsubaki,
• Reina Hara and
• Takashi Nishikata

Beilstein J. Org. Chem. 2020, 16, 502–508, doi:10.3762/bjoc.16.45

• alkene derivatives. Because an alkyne undergoes addition reaction at a C–C triple bond or cross-coupling at a terminal C–H bond. Combining those reaction patterns could realize a new reaction methodology to synthesize complex molecules including C–C multiple bonds. In this report, we found that the

• ; Introduction Terminal alkynes are undoubtedly useful functional groups for organic synthesis, and they can undergo a variety of reactions [1]. The C–C triple bond of an alkyne is suitable for addition reactions, whereas the terminal hydrogen atom is a good target for cross-coupling by using Sonogashira and

• . Although the exact reaction mechanism is currently unclear, one possibility involves a radical pathway including cross-coupling with an alkynyl copper species (Scheme 2). After the generation of A, addition of A to 1 takes place to give the radical intermediate B. This then reacts with the Cu(II) species

KOt-Bu-promoted selective ring-opening N-alkylation of 2-oxazolines to access 2-aminoethyl acetates and N-substituted thiazolidinones

• Qiao Lin,
• Shiling Zhang and
• Bin Li

Beilstein J. Org. Chem. 2020, 16, 492–501, doi:10.3762/bjoc.16.44

• to synthesize thiazolidinone derivatives through a Barton–McCombie pathway in 2015 [17] (Scheme 1b). Recently, potassium tert-butoxide has been shown to be an efficient promoter for C–C-bond formation reactions [18][19][20][21][22]. However, only few reports described C–N-bond cross-coupling

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• obtained in excellent yields of 93% and 97%, respectively, and represent potential substrates for subsequent cross-coupling reactions, which would provide structurally more complex products. Amidines with heterocyclic substituents were also evaluated. While the pyridine-substituted derivative 10o furnished

Synthesis of six-membered silacycles by borane-catalyzed double sila-Friedel–Crafts reaction

• Yafang Dong,
• Masahiko Sakai,
• Kazuto Fuji,
• Kohei Sekine and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2020, 16, 409–414, doi:10.3762/bjoc.16.39

• , the transformation of the amino groups in phenoxasilin 3a into phenyl groups was carried out (Scheme 5). First, the ammonium salt 4 was prepared by treating 3a with MeOTf followed by a palladium-catalyzed cross-coupling reaction with the Grignard reagent (PhMgBr) that afforded the desired diphenylated

Room-temperature Pd/Ag direct arylation enabled by a radical pathway

• Amy L. Mayhugh and
• Christine K. Luscombe

Beilstein J. Org. Chem. 2020, 16, 384–390, doi:10.3762/bjoc.16.36

• -conjugated materials, avoiding the prefunctionalization required for traditional cross-coupling methods. A major effort in organic electronic materials development is improving the environmental and economic impact of production; direct arylation polymerization (DArP) is an effective method to achieve these

Formal preparation of regioregular and alternating thiophene–thiophene copolymers bearing different substituents

• Atsunori Mori,
• Keisuke Fujita,
• Chihiro Kubota,
• Toyoko Suzuki,
• Kentaro Okano,
• Takuya Matsumoto,
• Takashi Nishino and
• Masaki Horie

Beilstein J. Org. Chem. 2020, 16, 317–324, doi:10.3762/bjoc.16.31

• head-to-tail (HT) orientation with respect to the substituent at the 3-position are extensively studied to date since they generally show superior performances as materials [1][2][3][4][5][6]. Cross-coupling polymerization catalyzed by a transition metal complex has been recognized as an effective tool

• . Cross-coupling polymerization of thiophene. Polymerization of bithiophene. Preparation of chlorobithiophenes. Polymerization of chlorobithiophenes. Funding This work was partially supported by JSPS Kakenhi B Grant Number JP19182273, Cooperative Research Program of “Network Joint Research Center for

Copper-promoted/copper-catalyzed trifluoromethylselenolation reactions

• Clément Ghiazza and
• Anis Tlili

Beilstein J. Org. Chem. 2020, 16, 305–316, doi:10.3762/bjoc.16.30

• could be trifluoromethylselenolated that way (Scheme 2) [13][15][16][17]. Mechanistically, the authors postulated the involvement of copper(I)/(III) oxidation states. Oxidative cross-coupling reactions between terminal alkynes using the [(bpy)CuSeCF3]2 complex were also undertaken by the same group to

• reagent was involved in several cross-coupling processes, including copper chemistry. In this context, in 2015, the group of Rueping reported an oxidative trifluoromethylselenolation process of terminal alkynes and boronic acid derivatives (Scheme 10) [27]. Using a stoichiometric amount of copper/ligand

• yields, as can be seen in Scheme 12 [35]. Due to the limitations of ClSeCF3 as an electrophilic reagent for trifluoromethylselenolations in cross-coupling reactions, our group developed a new bench-stable reagent, namely trifluoromethyltolueneselenosulfonate (TsSeCF3) [36

Synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin: experimental and computational evidence for intramolecular and intermolecular C–F···H–C bonds

• Vuyisa Mzozoyana,
• Fanie R. van Heerden and
• Craig Grimmer

Beilstein J. Org. Chem. 2020, 16, 190–199, doi:10.3762/bjoc.16.22

• cross-coupling reaction [17], Negishi cross-coupling reaction [18] and Wittig reaction [17]. The concept of the incorporation of fluorine into organic molecules has gained much interest since Fried and Sabo reported the improvement of the therapeutic index of cortisol by the incorporation of a fluorine

Allylic cross-coupling using aromatic aldehydes as α-alkoxyalkyl anions

• Akihiro Yuasa,
• Kazunori Nagao and
• Hirohisa Ohmiya

Beilstein J. Org. Chem. 2020, 16, 185–189, doi:10.3762/bjoc.16.21

• Akihiro Yuasa Kazunori Nagao Hirohisa Ohmiya Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan 10.3762/bjoc.16.21 Abstract The allylic cross-coupling using aromatic aldehydes as α-alkoxyalkyl anions is described

• -catalyzed allylic substitution. Keywords: aldehyde; copper; copper catalysis; cross-coupling; palladium; synthetic method; Introduction α-Alkoxy-substituted carbanions (α-alkoxyalkyl anions) are useful C(sp3) nucleophiles for the construction of alcohol units found in a majority of pharmaceuticals

• electrophile [8][10][11]. This paper describes in full detail the racemic system using allylic carbonates. The allylic cross-coupling of aromatic aldehydes and allylic carbonates with a silylboronate by the merging of a copper–N-heterocyclic carbene catalyst and a palladium–bisphosphine catalyst produced