Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• elimination of the palladium catalyst. Conclusion In summary, we have reported two one-pot pathways and two step-wise pathways to access dibenzodiazepinone (DBDAP) derivatives via copper-catalyzed Chan–Lam amination/carbonylative cyclization and Buchwald–Hartwig amination/carbonylative cyclization and their

• was via the Chan–Lam amination (milder conditions, cheaper, earth-abundant catalyst, no expensive ligand requirement) as the Buchwald–Hartwig amination required harsher conditions and an expensive metal catalyst, and also gave an unwanted phenazine side product. The sequential stepwise Chan–Lam

• sequential Buchwald–Hartwig amination/Pd-catalyzed carbonylative cyclization leading to DBDAPs.a Influence of the catalytic system, base, and solvent combination on the outcome of the Buchwald–Hartwig reaction.a The intramolecular catalytic carbonylative cyclization conditions for o-(2-bromophenyl

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• synthesised via a copper-catalysed Ullman-type coupling or a palladium-catalysed Buchwald–Hartwig amination (Scheme 9). Performing the rearrangement at high temperatures resulted in the undesirable formation of acridine byproducts 44. Cleaner reaction profiles could be obtained at a lower temperature (100 °C

• categorised according to the major or final catalytic step employed to form the 7-membered heterocycle as several synthetic methods use multiple catalytic steps. 3.1 Buchwald–Hartwig amination, etherification and thioetherification The Buchwald–Hartwig reaction gives access to arylamines, -ethers and

• -pyridobenzazepines 60b via cyclisation of 2,2'-dihalostilbene analogue 58 through a Pd-catalysed double Buchwald–Hartwig amination. The stilbene analogues 58 were prepared by a Wittig reaction with reported yields of the desired Z-isomer around 55%. The amination step was performed on a series of primary alkylamines

Substituent effect on TADF properties of 2-modified 4,6-bis(3,6-di-tert-butyl-9-carbazolyl)-5-methylpyrimidines

• Irina Fiodorova,
• Tomas Serevičius,
• Rokas Skaisgiris,
• Saulius Juršėnas and
• Sigitas Tumkevicius

Beilstein J. Org. Chem. 2022, 18, 497–507, doi:10.3762/bjoc.18.52

• -9H-carbazol-9-yl)-5-methyl-2-methylthiopyrimidine (tCbz-mPYR) as a starting material for the synthesis of 2-substituted pyrimidine emitters (Scheme 1). Compound tCbz-mPYR was synthesized by using the palladium-catalyzed Buchwald–Hartwig amination reaction of 4,6-dichloro-5-methyl-2-methylpyrimidine

Comparative study of thermally activated delayed fluorescent properties of donor–acceptor and donor–acceptor–donor architectures based on phenoxazine and dibenzo[a,j]phenazine

• Saika Izumi,
• Prasannamani Govindharaj,
• Anna Drewniak,
• Paola Zimmermann Crocomo,
• Satoshi Minakata,
• Leonardo Evaristo de Sousa,
• Piotr de Silva,
• Przemyslaw Data and
• Youhei Takeda

Beilstein J. Org. Chem. 2022, 18, 459–468, doi:10.3762/bjoc.18.48

• mono-functionalized compound DBPHZ-OTf, the target compound 1 was successfully synthesized through a Pd-catalyzed Buchwald–Hartwig amination with phenoxazine (POZ) in a good yield as red-brown solid (Scheme 1). The D–A–D counterpart POZ-DBPHZ was synthesized according to the previously reported process

Total synthesis of pyrrolo[2,3-c]quinoline alkaloid: trigonoine B

• Takashi Nishiyama,
• Erina Hamada,
• Daishi Ishii,
• Yuuto Kihara,
• Nanase Choshi,
• Natsumi Nakanishi,
• Mari Murakami,
• Kimiko Taninaka,
• Noriyuki Hatae and
• Tominari Choshi

Beilstein J. Org. Chem. 2021, 17, 730–736, doi:10.3762/bjoc.17.62

• synthesis of the 2,3-dihydroquinolin-4-one moiety of trigonoine B (1) by cycloamination of 22c (Scheme 4). The Buchwald–Hartwig amination of 22c was conducted in the presence of t-BuONa, BINAP, and Pd2(dba)3·CHCl3; however, the desired tetrahydroquinoline 23 was not obtained and only 22c was recovered. We

Synthesis, crystal structures and properties of carbazole-based [6]helicenes fused with an azine ring

• Daria I. Tonkoglazova,
• Anna V. Gulevskaya,
• Konstantin A. Chistyakov and
• Olga I. Askalepova

Beilstein J. Org. Chem. 2021, 17, 11–21, doi:10.3762/bjoc.17.2

• ethers of 3,6-diacetylcarbazole with p-benzoquinone (Scheme 1B) [49], the double Buchwald–Hartwig amination of 4,4'-biphenanthrene derivatives (Scheme 1C) [45] and a enantioselective Fischer indolization–oxidation protocol (Scheme 1D) [43]. Each method is not without drawbacks such as hardly available

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

• nitrogen heteroatoms were synthesized in multistep synthetic routes. A Buchwald–Hartwig amination of brominated precursors, thermolysis of azide precursors, and a Cadogan reaction of nitro-substituted precursors were successfully applied to eventually build-up pyrrole rings to stable and soluble fused

• replacement of sulfur by nitrogen atoms in the tetra- and hexacyclic systems leads to a red-shift in absorption, a decrease in oxidation potential and energy gap. On the other hand, the replacement of a thiophene ring by benzene leads to the opposite effects. Keywords: Buchwald–Hartwig amination; Cadogan

• -heteroacenes, dimeric thieno[3,2-b]pyrrole [8] and trimeric dithieno[3,2-b:2’,3’-d]pyrrole (DTP) [9], are long known but still frequently used as building block for organic electronic materials [10]. By application of Pd-catalyzed Buchwald–Hartwig amination/cyclization reactions of brominated thiophene-based

Plasma membrane imaging with a fluorescent benzothiadiazole derivative

• Pedro H. P. R. Carvalho,
• Jose R. Correa,
• Karen L. R. Paiva,
• Daniel F. S. Machado,
• Jackson D. Scholten and
• Brenno A. D. Neto

Beilstein J. Org. Chem. 2019, 15, 2644–2654, doi:10.3762/bjoc.15.257

•  1. The new fluorescent structure is accessible in a two-step procedure from the commercially available 4-bromo-2,1,3-benzothiadiazole (BTD-Br) and 4-aminopyridine (4AP), as we have recently described [41]. The Buchwald–Hartwig amination protocol afforded the fluorescent BTD-4AP in 80% yield after

Remarkable effect of alkynyl substituents on the fluorescence properties of a BN-phenanthrene

• Alberto Abengózar,
• David Sucunza,
• Patricia García-García and
• Juan J. Vaquero

Beilstein J. Org. Chem. 2019, 15, 1257–1261, doi:10.3762/bjoc.15.122

• -phenanthrene 1a [23]. Thus, an initial Buchwald–Hartwig amination between 2-bromo-5-chlorostyrene and 3-butenylamine was the initial step. This coupling was performed at 70 °C, as a higher yield was obtained at this temperature (71% at 80 °C, 24 h vs 82% at 70 °C, 48 h). Substrate 2 was then cyclized with

• reactions of 1b, under conditions optimized for a related BN-benzo[c]phenanthrene [30]. Gratifyingly, Suzuki coupling and Buchwald–Hartwig amination yielded the corresponding aryl- and amino-substituted BN-phenanthrenes 1c and 1d in good yields (Scheme 2). Moreover, Sonogashira couplings efficiently proceed

Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• -known biologically active analogs (Scheme 5) [3]. Pd-catalyzed reactions were effected on bromotriazolochromene 5e. The piperazin-1-ylchromenes have been identified to be potent inhibitors at the 5-HT1A receptor and at the 5-HT transporter [45][46]. Thus, Buchwald–Hartwig amination of 1-phenylpiperazine

The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

• Ildikó Bacsa,
• Dávid Szemerédi,
• János Wölfling,
• Gyula Schneider,
• Lilla Fekete and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 998–1003, doi:10.3762/bjoc.14.85

• with benzophenone imine and subsequent hydrogenolysis. Keywords: aminoestrones; Buchwald–Hartwig amination; 13α-estrone; functionalization; microwave assisted reactions; Introduction Aminoestrones are of particular interest thanks to their diverse biological applications [1][2][3][4]. There exist

• application of a Pd-catalyzed Buchwald–Hartwig amination. In recent years, extensive efforts have been made on the Pd(0)-catalyzed amination of aryl halides or triflates in order to achieve the efficient synthesis of substituted anilines [6][7][8][9]. Buchwald et al. stated that the Pd source is determining

• reported remarkable advantages of microwave-assisted syntheses, including shorter reaction times, higher yields and chemoselectivity [14][15][16]. Concerning the aromatic ring A of estrone, the Pd-catalyzed Buchwald–Hartwig amination was carried out exclusively at position C-3, starting from the 3-triflate

New electroactive asymmetrical chalcones and therefrom derived 2-amino- / 2-(1H-pyrrol-1-yl)pyrimidines, containing an N-[ω-(4-methoxyphenoxy)alkyl]carbazole fragment: synthesis, optical and electrochemical properties

• Daria G. Selivanova,
• Alexei A. Gorbunov,
• Olga A. Mayorova,
• Alexander N. Vasyanin,
• Igor V. Lunegov,
• Elena V. Shklyaeva and
• Georgii G. Abashev

Beilstein J. Org. Chem. 2017, 13, 1583–1595, doi:10.3762/bjoc.13.158

• ], Ullmann coupling [13][14], Buchwald–Hartwig amination [15] or N-alkylation of carbazole in the presence of alkali metal carbonates under MW irradiation [16]. In our case, the N-arylation was realized under phase transfer conditions using triethylbenzylammonium chloride (TEBA) as a catalyst [17][18

Nitration of 5,11-dihydroindolo[3,2-b]carbazoles and synthetic applications of their nitro-substituted derivatives

• Roman A. Irgashev,
• Nikita A. Kazin,
• Gennady L. Rusinov and
• Valery N. Charushin

Beilstein J. Org. Chem. 2017, 13, 1396–1406, doi:10.3762/bjoc.13.136

• of acetyl nitrate. Therefore, attempts to enhance yields of compounds 3 by using large amounts of acetyl nitrate have proved to be unsuccessful. Notably, 2,8-diamino-substituted ICZ derivatives have previously been prepared by using the Buchwald–Hartwig amination of the corresponding 2,8-dibromo-ICZs

Pd- and Cu-catalyzed approaches in the syntheses of new cholane aminoanthraquinone pincer-like ligands

• Nikolay V. Lukashev,
• Gennadii A. Grabovyi,
• Dmitry A. Erzunov,
• Alexey V. Kazantsev,
• Gennadij V. Latyshev,
• Alexei D. Averin and
• Irina P. Beletskaya.

Beilstein J. Org. Chem. 2017, 13, 564–570, doi:10.3762/bjoc.13.55

• macrocycles by Pd-catalyzed Buchwald–Hartwig amination [36]. Though this method is often preferable for the macrocyclization in comparison to classical nucleophilic substitution [28][31], it is limited to bile acid derivatives bearing groups with C(sp2)–Hal bonds. In addition, the use of bile acid moieties

• anthraquinones. Further attempts to apply the Cu-based catalytic system in this reaction with L-proline and other commonly used N,N, N,O, and O,O bidentate ligands were fruitless. Previously, some of us successfully used the classic conditions of the Buchwald–Hartwig amination for the preparation of bis-amino

Half-sandwich nickel(II) complexes bearing 1,3-di(cycloalkyl)imidazol-2-ylidene ligands

• Johnathon Yau,
• Kaarel E. Hunt,
• Laura McDougall,
• Alan R. Kennedy and
• David J. Nelson

Beilstein J. Org. Chem. 2015, 11, 2171–2178, doi:10.3762/bjoc.11.235

• NHC·HCl salt, rendering these species highly accessible (Scheme 1b) [10]. After the initial work by Cowley and Jones, various other researchers have disclosed complexes of this form and tested them in cross-coupling reactions such as Buchwald–Hartwig amination [11], Suzuki–Miyaura cross-coupling [12], and

A facile synthetic route to benzimidazolium salts bearing bulky aromatic N-substituents

• Gabriele Grieco,
• Olivier Blacque and
• Heinz Berke

Beilstein J. Org. Chem. 2015, 11, 1656–1666, doi:10.3762/bjoc.11.182

• with the preparation of the N1,N2-di(pyridine-2-yl)benzen-1,2-diamine (8). The Buchwald–Hartwig amination was applied in the syntheses of 5 and 6 where 1,2-dichlorobenzene was coupled with aniline and 2,4,6-trimethylaniline, respectively (Scheme 1). Attempting the synthesis of the N1,N2-bis(2,6

Tuning of tetrathiafulvalene properties: versatile synthesis of N-arylated monopyrrolotetrathiafulvalenes via Ullmann-type coupling reactions

• Vladimir A. Azov,
• Diana Janott,
• Dirk Schlüter and
• Matthias Zeller

Beilstein J. Org. Chem. 2015, 11, 860–868, doi:10.3762/bjoc.11.96

• excess cannot be considered a disadvantage of the method. Additionally, use of the inexpensive Cu(I) catalyst allows to avoid Buchwald–Hartwig amination [24][25], which employs more expensive Pd-based catalysts for a similar type of C–N coupling reactions. In a typical procedure, 1 equiv of MPTTF 7a, 7b

Redox active dendronized polystyrenes equipped with peripheral triarylamines

• Toshiki Nokami,
• Naoki Musya,
• Tatsuya Morofuji,
• Keiji Takeda,
• Masahiro Takumi,
• Akihiro Shimizu and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2014, 10, 3097–3103, doi:10.3762/bjoc.10.326

• examined before studying the functionalization of dendronized polystyrene. Thus, di(p-methoxyphenyl)amino groups were introduced to 4 using a Buchwald–Hartwig amination [11]. The choice of a base is crucial for this transformation, and the transformation was successfully carried out using Cs2CO3 as a base

Visible light mediated intermolecular [3 + 2] annulation of cyclopropylanilines with alkynes

• Theresa H. Nguyen,
• Soumitra Maity and
• Nan Zheng

Beilstein J. Org. Chem. 2014, 10, 975–980, doi:10.3762/bjoc.10.96

• -iodobenzene (19) and cycloproylamine, 2-bromo-N-cyclopropylaniline (20) was prepared in 75% yield via the Buchwald–Hartwig amination [39][40]. The [3 + 2] annulation of 2-bromo-N-cyclopropylaniline (20) and phenylacetylene (2) was performed using the optimized catalyst system to provide cyclic allylic amine

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

Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

• Torsten Dittrich,
• Nils Hanekop,
• Nacera Infed,
• Lutz Schmitt and
• Manfred Braun

Beilstein J. Org. Chem. 2012, 8, 1700–1704, doi:10.3762/bjoc.8.193

• precursor 2c was obtained by an N-arylation, as described in the literature.[21] A modified Buchwald–Hartwig amination reaction using tri-tert-butylphosphane as a ligand at palladium [22] was applied in order to couple 4-methylphenyl bromide and 4-fluorophenyl bromide with Boc-protected aminopiperidines 17

Extending the utility of [Pd(NHC)(cinnamyl)Cl] precatalysts: Direct arylation of heterocycles

• Anthony R. Martin,
• Anthony Chartoire,
• Alexandra M. Z. Slawin and
• Steven P. Nolan

Beilstein J. Org. Chem. 2012, 8, 1637–1643, doi:10.3762/bjoc.8.187

• ) (Figure 1). Complexes 1 and 2 are commercially available and have proven to be highly efficient in Suzuki–Miyaura coupling and Buchwald–Hartwig amination reactions [17][18][19][20]. We have also evaluated the recently reported [Pd(IPr*)(cin)Cl] (3), which has shown potency in Suzuki–Miyaura couplings [21

Double N-arylation reaction of polyhalogenated 4,4’-bipyridines. Expedious synthesis of functionalized 2,7-diazacarbazoles

• Mohamed Abboud,
• Emmanuel Aubert and
• Victor Mamane

Beilstein J. Org. Chem. 2012, 8, 253–258, doi:10.3762/bjoc.8.26

• -diazacarbazole by using a palladium-catalyzed double N-arylation of 4,4’-dichloro-3,3’-bipyridine, itself obtained after a long reaction sequence [25][26][27]. In another patent, an intramolecular Buchwald–Hartwig amination [28][29] was used to generate a 2,7-diazacarbazole derivative in low yield [30]. Recently

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• preparation of various 2,3-disubstituted indole derivatives 62 (Scheme 27). Amines as coupling partners through Buchwald–Hartwig amination Other strategies used for the palladium-mediated three-component preparation of substituted indole derivatives involve an efficient Buchwald–Hartwig amination as the key

• coupling leading to a mono-alkynylated product, followed by an intermolecular Buchwald–Hartwig amination and a subsequent intramolecular amination. This Pd-catalyzed tandem coupling reaction allows the preparation of a variety of 2-alkynylindoles 64 (Scheme 28). An elegant three-component process based on

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• -aryl bond formation, and many examples illustrate their wide application in organic synthesis. The chelating phosphines BINAP, DPPF [17] and DtBPF [18], commonly used for the Buchwald–Hartwig amination, were recently displaced by the biaryl-(dialkyl)phosphine or arylphosphinepyrrole ligands [18][19][20

• ]. Industrial scale-up of these methods has already been applied on the 100 kg scale for arylpiperazines and different diarylamines [21]. In addition, Nolan et al. and Organ et al. have reported Pd-N-heterocyclic carbene (NHC)-catalysed Buchwald–Hartwig amination protocols that provide access to a range of