Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• heteroaromatic halides. The reaction sequence utilizes a photochemically enhanced Negishi cross-coupling as a key step, followed by oximation and reduction. The prepared amino esters were validated for on-DNA reactivity via a reverse amidation–hydrolysis–reverse amidation protocol. Keywords: amino acids; DEL

• that α-heteroaryl acetates accessed through Negishi coupling can be used as key intermediates towards NCAs (Scheme 1c). Indeed, oximation of these motifs followed by reduction gave access to the desired NCAs. Results and Discussion Negishi cross-coupling step The Negishi reaction provides convenient

• , Alcazar et al. developed continuous flow protocols for both the generation of alkylzinc halides and for the subsequent Negishi cross-coupling reaction [40][41][42][43][44]. We successfully adapted Alcazar’s protocols for the synthesis of otherwise challenging heteroaryl–alkyl connections (see Table S1 in

Facile access to pyridinium-based bent aromatic amphiphiles: nonionic surface modification of nanocarbons in water

• Lorenzo Catti,
• Shinji Aoyama and
• Michito Yoshizawa

Beilstein J. Org. Chem. 2024, 20, 32–40, doi:10.3762/bjoc.20.5

• -dibromopyridine. Negishi cross-coupling with 9-anthrylzinc chloride in the presence of PdCl2(PhCN)2/P(t-Bu)3 as catalyst afforded the common precursor 3,5-dianthrylpyridine (prePA), a simple yet novel bent building block, in 81% yield. For the synthesis of the methyl derivative, prePA was N-alkylated with excess

Biphenylene-containing polycyclic conjugated compounds

• Cagatay Dengiz

Beilstein J. Org. Chem. 2023, 19, 1895–1911, doi:10.3762/bjoc.19.141

• the synthesis of compound 81 through the utilization of the Negishi cross-coupling reaction and then the removal of TMS groups from this intermediate was achieved using TBAF, resulting in the formation of diyne 82 in 65% yield. The progression towards the synthesis of biphenylene-containing substrate

Total synthesis of insect sex pheromones: recent improvements based on iron-mediated cross-coupling chemistry

• Eric Gayon,
• Guillaume Lefèvre,
• Olivier Guerret,
• Adrien Tintar and
• Pablo Chourreu

Beilstein J. Org. Chem. 2023, 19, 158–166, doi:10.3762/bjoc.19.15

• nucleophilic partner R[M] in a cross-coupling has been reported in the recent literature. It was indeed shown that some ligands (such as diphosphines) used in Fe-catalyzed Negishi cross-coupling reactions (R[M] = RZnX) were actually involved in the coordination of the ZnII cation in a key on-cycle

Synergy between supported ionic liquid-like phases and immobilized palladium N-heterocyclic carbene–phosphine complexes for the Negishi reaction under flow conditions

• Edgar Peris,
• Raúl Porcar,
• María Macia,
• Jesús Alcázar,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2020, 16, 1924–1935, doi:10.3762/bjoc.16.159

• cross-coupling; NHC complex; palladium; supported ionic liquid; Introduction N-heterocyclic carbenes (NHCs) are known as efficient coordination ligands for different types of metals. The main feature of NHC complexes is their structural tunability [1]. Thus, their catalytic efficiency can be easily

• of the NHC–Pd catalyst and the SILLPs is a key factor for the optimization of the release and catch mechanism leading to a catalytic system easily recoverable and reusable for a large number of catalytic cycles enhancing the long-term catalytic performance. Keywords: immobilized catalyst; Negishi

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

• of the corresponding Grignard intermediate in the presence of ZnCl2 and LiCl, which were subsequently used in Negishi cross-coupling reactions [41]. The most recent example, by the Löb group, reported a pilot plant reactor including a Mg replenish unit that allowed to generate phenylmagnesium bromide

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

• involved a Negishi cross coupling of an aryl halide and the Zn homoenolate of the protected (R)-iodoalanine 2 using a Pd(0) catalyst. This method provided a versatile range of fluorinated phenylalanine products with high enantioselectivities and in acceptable yields. 2. Synthesis of β-fluorophenylalanines

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

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• ]. Reaction of allyl iodide (17) with metalated 9d after addition of catalytic amounts of CuCN∙2LiCl led to the formation of the 5-allyl compound 18 in 37% yield. Metalation of 9d using TMPMgCl∙LiCl and subsequent transmetalation with ZnCl2 followed by Negishi cross-coupling reaction in the presence of Pd(dba

Borylation and rearrangement of alkynyloxiranes: a stereospecific route to substituted α-enynes

• Ruben Pomar Fuentespina,
• José Angel Garcia de la Cruz,
• Gabriel Durin,
• Victor Mamane,
• Jean-Marc Weibel and
• Patrick Pale

Beilstein J. Org. Chem. 2019, 15, 1416–1424, doi:10.3762/bjoc.15.141

• ]. Alternatively, Unemaya et al. and more recently Buchwald et al. described a Negishi cross coupling of aryl bromides or chlorides to α-CF3-oxiranyl zincates generated by lithiation of trifluoromethyloxirane and transmetalation with zinc chloride [10][11]. In this context and based on the pioneering work of

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• , geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide and an (E)-iodoalkene that was synthesized via an aluminium ester enolate attack at (R)-propylene oxide. The overall synthesis comprises nine steps with an overall yield

• sp3–sp2 Negishi cross coupling. The required organozinc reagent 8 has been applied occasionally and is accessible from the corresponding commercially available chiral bromide [30][31][32][33][34]. The coupling partner would be an (E)-iodoalkene that was to be constructed from enantiomerically pure (R

• published a route to a 1:1 mixture of diastereomers of a TBS-protected analogue of building block 18 [41]. Negishi cross coupling of sp3 organozinc homoenolate 8 (2.75 equiv) and iodoalkene 18 (10 mol % [Pd(dppf)Cl2 × DCM] in DCM) afforded a satisfying 75% yield of the protected nonenoic acid 20 (Scheme 3

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

• ) derivatives and dipeptides. In this regard, trimerization and Negishi cross-coupling reactions are used as the key steps starting from readily available 4’-iodoacetophenone and L-serine. These C3-symmetric molecules containing AAA moieties are useful to design new ligands suitable for asymmetric synthesis and

• electroluminescent devices [33]. To address these challenges, we [34] and others [35][36] have synthesized functionalized C3-symmetric molecules containing amino acids and peptides. The Negishi cross coupling [37][38] is a reliable synthetic method, which involves palladium or nickel-catalyzed coupling of organozinc

• knowledge only a limited number of reports is available for the synthesis of C3-symmetric peptides (Figure 1) [8][41]. To fill this gap, we have explored a new synthetic strategy to star-shaped C3-symmetric AAA derivatives and peptides by using trimerization and the Negishi cross coupling as key steps

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• ], published in 2007, Kishi and co-workers increased the overall efficiency of the synthesis by reorganizing the assembly of the principal fragments and by optimizing the key C(sp2)–C(sp3) Negishi cross-coupling reactions as well as the choice of protecting groups. The 3rd generation approach [123], published

• mycolactone core structure is depicted in Scheme 1. It relied on two consecutive Negishi cross-coupling reactions [124] to construct the linear C1–C20 fragment, which was to be cyclized by macrolactonization [39]. Vinyl iodide 19, corresponding to the C14–C20 part of the core extension, was synthesized from

• moiety. The synthesis of alkyl iodide 23 departed from TBS-protected 5-hydroxypentanal 22 and proceeded via an asymmetric Brown crotylation to establish the C5 and C6 stereocenters. Intermediates 21 and 23 were combined under Smith’s modified [134] Negishi cross-coupling [124] conditions to furnish the

A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

• Benedikt C. Melzer and
• Franz Bracher

Beilstein J. Org. Chem. 2017, 13, 1564–1571, doi:10.3762/bjoc.13.156

• species with ZnCl2 should lead to at C-1 zincated isoquinolines, which could undergo Negishi cross-coupling reactions with appropriately substituted methyl 2-bromobenzoates to give methyl 2-(isoquinolin-1-yl)benzoates. These would again open an access to oxoisoaporphine alkaloids via intramolecular

• extended to 6-methoxyisoquinoline (7c). Unfortunately, transmetalation with ZnCl2 at 0 °C followed by palladium-catalyzed (5 mol % Pd(dba)2/ 10 mol % P(2-furyl)3 or 1 mol % Pd2(dba)3/2 mol % RuPhos) Negishi cross-coupling reaction with methyl 2-bromo-5-methoxybenzoate did not lead to the expected methyl 2

Synthesis of the heterocyclic core of the D-series GE2270

• Christophe Berini,
• Thibaut Martin,
• Pierrik Lassalas,
• Francis Marsais,
• Christine Baudequin and
• Christophe Hoarau

Beilstein J. Org. Chem. 2017, 13, 1407–1412, doi:10.3762/bjoc.13.137

• of thiopeptides GE2270 in which the macrocylization and heterocyclic core was simultaneously achieved through a late-stage Negishi cross-coupling [18][19]. Last year, Yamaguchi’s group proposed a novel elegant [4 + 2] cycloaddition Kondrat’eva reaction between a 2-alkenylated thiazole-4-carboxylate

A concise and practical stereoselective synthesis of ipragliflozin L-proline

• Shuai Ma,
• Zhenren Liu,
• Jing Pan,
• Shunli Zhang and
• Weicheng Zhou

Beilstein J. Org. Chem. 2017, 13, 1064–1070, doi:10.3762/bjoc.13.105

• Negishi cross-coupling of arylzinc with protected glycosyl bromide in the presence of Ni-catalysts. An improved procedure with high stereoselectivity and in the absence of catalysts was reported subsequently by Lemarie et al. (Scheme 1) [12] to construct the anomeric chiral center of dapagliflozin and

Synthesis of tetrasubstituted pyrazoles containing pyridinyl substituents

• Josef Jansa,
• Ramona Schmidt,
• Ashenafi Damtew Mamuye,
• Laura Castoldi,
• Alexander Roller,
• Vittorio Pace and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2017, 13, 895–902, doi:10.3762/bjoc.13.90

• corresponding 1,3,5-trisubstituted pyrazoles. Iodination at the 4-position of the pyrazole nucleus by treatment with I2/HIO3 gives the appropriate 4-iodopyrazoles which served as starting materials for different cross-coupling reactions. Finally, Negishi cross-coupling employing organozinc halides and Pd

• -diketones with arylhydrazines, halogenation of the resulting 1,3,5-triarylpyrazoles in the 4-position and further functionalization via Negishi cross-coupling [23][24] or halogen–lithium exchange reaction (Scheme 1). The resulting compounds amongst others seem to be interesting as potential complexing

• the main product, but also containing biphenyl, traces of the desired product 6a, the homocoupling dimer 7a as well as a compound 8, obviously resulting from attack of PhLi to the pyridine system attached to pyrazole N-1 (Scheme 4). Negishi cross-couplings with 4-iodopyrazoles 3a–d The Negishi cross

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• telescoped homocatalysis procedure consisting of a three-step sequence (metalation, zincation and Negishi cross-coupling) which furnishes an easy access to a variety of functionalized 2-fluorobiaryl and heteroaryl products (Scheme 9) [59]. This strategy is rightfully considered green because it guarantees

• products. Experimental setup for the flow synthesis of 2-fluorobi(hetero)aryls by directed lithiation, zincation, and Negishi cross-coupling. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim). Experimental setup for the coupling of fluoro-substituted pyridines

A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki–Miyaura cross-coupling reaction

• Dariusz Błachut,
• Joanna Szawkało and
• Zbigniew Czarnocki

Beilstein J. Org. Chem. 2016, 12, 835–845, doi:10.3762/bjoc.12.82

• leading to a number of different 2,4- and 2,5-diaryldimethylpyridines P3, P4 [25], 4-benzylpyrimidines P2 [26], and 4-methyl-5-arylpyrimidines P1 [26] was needed. For this purpose, we successfully used Suzuki and Negishi cross-coupling reactions between arylboronic acids/benzylzinc reagents and

Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity

• Louis P. Sandjo,
• Victor Kuete and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183

• successfully performed in six steps with an overall yield of 6.5%. The steps included an organometallic intermediate and a Negishi cross-coupling reaction characterized by a transmetalation with zinc and palladium. The benzonaphthyridinone product was transformed into a bromobenzonaphthyridine intermediate by

• using phosphoryl bromide. Another organozinc substrate was coupled to the obtained intermediate by a Negishi cross-coupling and cyclisation occurred to give the expected secondary metabolite (Scheme 8) [68]. The yield of the last step in the preparation of 9 could be improved by using the synthetic

Molecular recognition of isomeric protonated amino acid esters monitored by ESI-mass spectrometry

• Andrea Liesenfeld and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 825–831, doi:10.3762/bjoc.10.78

• started from 1-bromo-4-methoxybenzene which was transferred into 2-bromo-4’-methoxybiphenyl (3) in 92% yield via lithiation with t-BuLi, transmetallation with zinc(II) bromide, and subsequent Negishi cross-coupling reaction with 1-bromo-2-iodobenzene [14][15]. 3 was then transformed into the corresponding

Towards allosteric receptors – synthesis of β-cyclodextrin-functionalised 2,2’-bipyridines and their metal complexes

• Christopher Kremer,
• Gregor Schnakenburg and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 814–824, doi:10.3762/bjoc.10.77

• -coupling reaction in excellent yields [26]. The non-symmetric 4,6’-disubstituted bipyridine 10 was obtained in good yield from a Negishi cross-coupling of 6 and 7 [27]. Cleavage of the pyrrole protecting groups of 8–10 with hydroxylamine provided the corresponding diamines 11–13 [26] in satisfying to

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• then by the Negishi cross coupling to produce silylated product 254a, which was desilylated to obtain alcohol 255a (Scheme 72). 1,2-Dioxane 255a is structurally similar to natural peroxyplakoric acids having fungicidal and antimalarial activities [332]. 3.8. Use of halonium ions in the cyclization This

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• recently reported an approach to forming the first aryl–aryl C–C bond by a directed lithiation of a pyridine 1.91 followed by conversion to its organozinc derivative. This intermediate then undergoes a high-yielding Negishi cross-coupling reaction with an arylbromide (Scheme 17) [52]. After acidic

Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

• Wafa Gati,
• Mohamed M. Rammah,
• Mohamed B. Rammah and
• Gwilherm Evano

Beilstein J. Org. Chem. 2012, 8, 2214–2222, doi:10.3762/bjoc.8.250

• isolated in modest yields (30–33%), even in the presence of additional HMPA, which might may constitute the major limitation of our process. Other attempts involving electrophiles such as acid chlorides and allyl bromide or transmetallation with zinc chloride and Negishi cross-coupling were unsuccessful