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

• acids with high enantiomeric purity [23]. The synthesis of formally glycine-derived tertiary α-aryl-amino acids is much less developed. The most common strategy for obtaining these substrates is by lithiation of an aromatic ring followed by coupling with a glycine derivative (Scheme 1a). For example

Competing electrophilic substitution and oxidative polymerization of arylamines with selenium dioxide

• Vishnu Selladurai and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2024, 20, 1221–1235, doi:10.3762/bjoc.20.105

• interest [12][13]. The various approaches used for selenation of aromatic compounds include directed lithiation [14][15], copper-catalyzed selenation [16][17][18], and aromatic nucleophilic substitution reactions [19][20][21][22]. Electrophilic selenium reagents (e.g., phenylselenenyl bromide) have often

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• . Although olefin 3 has been available for many decades, only one paper describes its lithiation with methyllithium and the subsequent reaction of the lithium compound with trifluoroacetophenone [27]. We began our research on the reactivity of the bromobutenes 3a,b with isopropylmagnesium chloride (iPrMgCl

• increase the lithiation reaction time. Based on the results obtained, it was logical to assume that the reaction can be carried out with a mixture of 3a,b. We found that the reaction of 3a,b with 1.2 equivalents of BuLi in heptane at −80 °C for 1 hour, followed by warming to room temperature, led to the

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• between carboranes and chalcogen-doped π-conjugated heterocycles, Yang and co-workers devised a two-step strategy for the synthesis of carborane-fused thiophene 43 (Scheme 11, bottom) [72]. Double lithiation of carboranyl indole 41 was followed by trapping with disulfur dichloride as chalcogen source to

Biphenylene-containing polycyclic conjugated compounds

• Cagatay Dengiz

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

• -dibora-2,5-cyclohexadiene structure (Scheme 16) in addition to a π-extended linear POA (Scheme 17) [50]. The preparation of v- and z-shaped POAs 77 and 78 was carried out starting from 2-bromobiphenylene (74). Initial steps involved ortho-directed lithiation and subsequent treatment with Me3SiCl

Thienothiophene-based organic light-emitting diode: synthesis, photophysical properties and application

• Recep Isci and
• Turan Ozturk

Beilstein J. Org. Chem. 2023, 19, 1849–1857, doi:10.3762/bjoc.19.137

• polyphosphoric acid (PPA) in refluxing chlorobenzene to give 3 (TT) in 86% yield. The brominated TT 4 was obtained through selective monobromination of compound 3 using NBS at −10 °C in DMF in 88% yield. The boronated triphenylamine 6 was constructed in a one-pot two-step reaction in 77% yield, by lithiation of

• lithiation of 7 and following reaction with dimesitylboron fluoride in 85% yield (Scheme 1). Photophysical properties The UV–vis absorption and fluorescence spectra of DMB-TT-TPA (8) were recorded in THF (Figure 1 and Table 1) [38]. It showed maximum absorption and emission wavelengths of 411 and 520 nm

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• allylation of lithium (trimethylsilyl)amides prepared in situ from the parent amines by a lithiation/silylation/lithiation sequence (Table 1). Using this protocol, α-(aminomethyl)acrylates 5 and 6 derived from benzhydrylamine and aniline were prepared in high yields (Table 1, entries 1 and 2). The procedure

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• 21 cannot be lithiated to give a stable vinyllithium species, and immediately expel a sulfide anion to afford phenylthioacetylene (Scheme 6a) [40], Brandsma showed that the lithiated derivatives of 1,4-dithiin (3) can be generated by ‘ortho-lithiation’-type reactions at −110 °C in THF (Scheme 6d) [41

• opens up options for Corey–Seebach-type alkylation reactivity with a wider range of electrophiles. The method is demonstrated by the smooth lithiation and subsequent alkylation of the acetophenone-derived dithiin 50 (Scheme 10a) [42]. Palumbo’s elegant overall approach to dihydrodithiin-mediated

• ]. The alkylation of dihydrodithiins via lithiation and reaction with electrophiles is quite versatile, as shown by the examples above, but is still limited in scope, especially compared to 1,3-dithianes. This is mainly due to the still limited stability of the lithiated species (vide supra), limiting

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

• the Ortiz group investigated the directed ortho-lithiation of aminophosphazenes, they realized one example synthesis of (R)-1-phenyl-2-((R)-1-phenylethyl)-2-hydrobenzo[c][1,2]azaphosphol-3-one 1-oxide (239) from methyl (R)-(diphenyl((1-phenylethyl)amino)-λ5-phosphanylidene)carbamate (237) via the

• ortho-directed lithiation with tert-butyllithium with carbamate as the directing group followed by electrophilic quench with methyl chloroformate and intramolecular aminolysis. Finally, hydrolysis removed the directing group, affording the final product 239 in 50% yield (Scheme 38) [59]. Structurally

• of (R)-1-phenyl-2-((R)-1-phenylethyl)-2-hydrobenzo[c][1,2]azaphosphol-3-one 1-oxide (239) from methyl (R)-(diphenyl((1-phenylethyl)amino)-λ5-phosphanylidene)carbamate (237) via ortho-directed lithiation followed by electrophilic quench and intramolecular aminolysis. Synthesis of dihydro[1,2

Allylic alcohols and amines by carbenoid eliminative cross-coupling using epoxides or aziridines

• Matthew J. Fleming and
• David M. Hodgson

Beilstein J. Org. Chem. 2021, 17, 2385–2389, doi:10.3762/bjoc.17.155

• alkoxide. Keywords: alkenes; aziridines; epoxides; lithiation; synthetic methods; Introduction Methods for the convergent generation of alkenes can be of significant utility in organic synthesis [1]. A relatively under-examined approach is through the interaction of two carbenoids [2]. Dimerisation of

• alkene 12 (30%) could be formed from terminal epoxide 5, using cyclopropylstannane 11 [16] (Scheme 5); in this case the presence of LTMP was also necessary as epoxide 5 was recovered (>80%) in its absence. A silyl-stabilised methoxymethyllithium, available by direct lithiation of (methoxymethyl

• )trimethylsilane (13) [17], gave vinylsilane 14 (26%, E/Z = 81:19) on reaction with terminal epoxide 5 in the presence of LTMP (Scheme 6); the allylic alcohol 6 was also isolated (20%), suggesting that in our hands lithium–trimethylsilyl exchange competes with lithiation of (methoxymethyl)trimethylsilane (13

Cascade intramolecular Prins/Friedel–Crafts cyclization for the synthesis of 4-aryltetralin-2-ols and 5-aryltetrahydro-5H-benzo[7]annulen-7-ols

• Jie Zheng,
• Shuyu Meng and
• Quanrui Wang

Beilstein J. Org. Chem. 2021, 17, 1481–1489, doi:10.3762/bjoc.17.104

• Scheme 3 consisting of the following steps: (i) Wittig reaction of 2-bromobenzaldehyde with methyltriphenylphosphonium iodide ylide, (ii) lithiation of the resultant o-bromostyrene with n-BuLi and reaction of the aryl lithium species with ethylene oxide, and (iii) oxidation of the resultant primary

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• vinylogous Mukaiyama aldol reaction to produce the desired aldehyde (rac)-118 in 81% yield. Meanwhile, the TIPS protection of oxazole 119 and then subsequent lithiation at the C-5 position and quenching in situ with allyl bromide furnished oxazole derivative 121 in 90% yield (Scheme 16). An attempted cross

Synthesis and characterization of S,N-heterotetracenes

• Astrid Vogt,
• Florian Henne,
• Christoph Wetzel,
• Elena Mena-Osteritz and
• Peter Bäuerle

Beilstein J. Org. Chem. 2020, 16, 2636–2644, doi:10.3762/bjoc.16.214

• -dibromothiophene 6 and Pd(dppf)Cl2 as catalyst to give the corresponding dibromide 7 in a yield of 70%. Organozinc species 6 was obtained from 2,3-dibromothiophene by lithiation with n-BuLi and reaction with zink dichloride. Annulation to TIPS-protected SN4-Hex 8 was achieved in 87% yield by a tandem Buchwald

• step, an azide group was introduced to 10 by lithiation with n-BuLi followed by the reaction with tosyl azide giving azide 11 in an excellent yield of 92%. Thermally induced ring-closure under release of nitrogen and formation of a nitrene intermediate was achieved by refluxing azide 11 in

• -substituted thienopyrrole 26, saponification to carbonic acid 27, and subsequent Cu-mediated decarboxylation in quinoline resulted in thienopyrrole 28 in more than 80% yield over three steps. Lithiation of 28 with n-BuLi and reaction with TIPS chloride selectively occurred at the thiophene α-position to give

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

Synthesis of 6,13-difluoropentacene

• Matthias W. Tripp and
• Ulrich Koert

Beilstein J. Org. Chem. 2020, 16, 2136–2140, doi:10.3762/bjoc.16.181

• subsequent reduction of the anthraquinone gave 1,4-difluoroanthracene. After ortho-lithiation and reaction with phthalic anhydride a carboxylic acid was obtained whose Friedel–Crafts acylation and subsequent reductive removal of the oxygen-functionalities resulted in the formation of the target compound. The

• HOMO–LUMO gap of 6,13-difluoropentacene was determined via UV–vis spectroscopy and compared to other fluorinated pentacenes. Keywords: fluorinated acenes; Friedel–Crafts reaction; ortho-lithiation; synthesis; Introduction Pentacenes are a prototype in the field of organic semiconductors due to their

• acid precursor could be prepared by reaction of the anthracenyllithium 7 with phthalic anhydride (8). Intermediate 7 could be accessed by ortho-lithiation of anthracene 9. The synthesis of 9 by two consecutive Friedel–Crafts acylation reactions and reduction of the resulting anthraquinone could start

Clickable azide-functionalized bromoarylaldehydes – synthesis and photophysical characterization

• Dominik Göbel,
• Marius Friedrich,
• Enno Lork and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2020, 16, 1683–1692, doi:10.3762/bjoc.16.139

• -methylbenzaldehyde). Bromofluorenecarbaldehyde 5 The synthetic route to azide-functionalized 7-bromofluorene-2-carbaldehyde 5 started from unfunctionalized fluorene. Double bromination to 14, followed by double methylation of the methylene bridge to 15 and a lithiation/formylation sequence afforded 7-bromofluorene-2

Rearrangement of o-(pivaloylaminomethyl)benzaldehydes: an experimental and computational study

• Csilla Hargitai,
• Györgyi Koványi-Lax,
• Tamás Nagy,
• Péter Ábrányi-Balogh,
• András Dancsó,
• Gábor Tóth,
• Judit Halász,
• Angéla Pandur,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2020, 16, 1636–1648, doi:10.3762/bjoc.16.136

• of the two functional groups cannot be observed in this case, we could focus on the formation of the dimer-like products. Treatment of unsubstituted derivative 1e (prepared from bromo derivative 21 [26] by formylation via lithiation) in DCM in the presence of a catalytic amount (0.1 equiv) of TFA for

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• . Optimisation of the use of this base was then investigated further (Table 2). An optimal deprotonation and phosphorylation was found to occur when an excess (3 equiv) of base was used at −42 °C (Table 2, entry 4), with a lithiation time of 20 min. The addition of TMEDA was detrimental to this conversion with a

• with CD3OD by 1H and 13C NMR spectroscopy indicated the formation of the monolabelled compound 17 as the major product, demonstrating that lithiation only occurs at a single position of compound 13 (Scheme 6). When performed on a multigram scale, phosphonate 7 was isolated in 68% yield after

• phosphoramidate protecting group, which was superior to the more commonly applied Boc protecting group which was unstable to the lithiation. This synthetic route replaces traditional Wittig and tandem alkylation/reduction methodologies, which suffer from complications arising from troublesome byproducts and

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• 57. Coupling of 57 with Ph2PCl·BH3 resulted in the boron-protected ligand 58, which was deprotected with Et3N. Alternatively, 1,1’-bis(diphenylphosphino)ferrocene (dppf) with palladium(II) acetate was used to catalyze the reduction of 55 generating the pyridine scaffold 57. Subsequent lithiation and

• magnesium-containing triazoles 66 which, upon quenching with ammonium chloride, afforded the triazoles 67. Lithiation followed by coupling with the appropriate chlorophosphines resulted in the desired 1,5-disubstitued triazolylphosphine ligands 68. The procedure could be performed in one pot by directly

• is dependent on the inductive and/or steric effects of the substituents present on the backbone [75][76]. The α-phosphorus methylene lithiation presents more prospects for the development of modified 1,3,5-triaaza-7-phosphaadamantane (PTA) ligands [77][78]. A chiral center is also introduced adjacent

A green, economical synthesis of β-ketonitriles and trifunctionalized building blocks from esters and lactones

• Daniel P. Pienaar,
• Kamogelo R. Butsi,
• Amanda L. Rousseau and
• Dean Brady

Beilstein J. Org. Chem. 2019, 15, 2930–2935, doi:10.3762/bjoc.15.287

• cyclohexyl 15 (68%) analogues. We were pleased to obtain the highly versatile and synthetically useful cinnamoylacetonitrile 17 [20] from renewable ethyl cinnamate in 64% yield, as this yield was comparable to more expensive and hazardous lithiation protocols [7]. Finally, we attempted method optimization

A new approach to silicon rhodamines by Suzuki–Miyaura coupling – scope and limitations

• Thines Kanagasundaram,
• Antje Timmermann,
• Carsten S. Kramer and
• Klaus Kopka

Beilstein J. Org. Chem. 2019, 15, 2569–2576, doi:10.3762/bjoc.15.250

• 30b to rhodamine 30c clearly outperforms the addition of lithiated 2-bromothiophene to xanthone 12 since 2-bromothiophene might also undergo lithiation in 5-position in competition to the halogen metal exchange (in general multiple halogenated aryls are problematic nucleophiles for these addition

Synthesis of a dihalogenated pyridinyl silicon rhodamine for mitochondrial imaging by a halogen dance rearrangement

• Jessica Matthias,
• Thines Kanagasundaram,
• Klaus Kopka and
• Carsten S. Kramer

Beilstein J. Org. Chem. 2019, 15, 2333–2343, doi:10.3762/bjoc.15.226

• initiate the HD reaction, 3-bromo-2-chloropyridine (19) had first to be lithiated. After 30 min at −78 °C, the silicon xanthone 17 was added at the same temperature and the reaction mixture was subsequently warmed up to room temperature and stirred for varying time periods. By using t-BuLi as a lithiation

• of the base is used for the lithiation, while a second equivalent base eliminates hydrogen bromide from the resulting t-BuBr. Therefore, entries 2 and 3 (Table 2) represent the use of approx. 0.5 equiv base for 1 equiv of 19. After lithiation of 19, the metallated intermediate (2-chloropyridin-3-yl

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• triptolide (Figure 2, route I and Scheme 7) [74]. In this synthesis, commercially available 2-isopropylphenol (31) was used as starting material, protection of 31 with chloromethyl methyl ether (MOM), followed by ortho lithiation and methylation with iodomethane, provided intermediate 85, which was lithiated

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

• tetrasubstituted alkenes [6][7]. Capitalizing on these precedents, Aggarwal et al. showed that oxiranes could be homologated to diols through lithiation, borylation, rearrangement and oxidation of the so-formed β-hydroxyboranes [8]. More recently, Blakemore et al. applied this sequence to sulfinyloxiranes [9

• ]. 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

• the above results, we conclude that the alkynyloxirane-to-enyne reaction is stereospecific, maintaining the stereochemistry of the starting oxirane in the resulting enyne. This stereospecificity imposes the stereochemical integrity of the oxiranyllithium species formed upon lithiation, but also the