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

• as readily available starting material. Keywords: antibiotic; bromination; BSC; C–H arylation; cross-coupling; Hantzsch synthesis; thiopeptide; Introduction Thiopeptide antibiotics are a class of peptide-derived macrocycles which contain many thiazole and thiazoline units, with almost 90 structures

• with a sophisticated tris-1,3-diazole, judiciously prepared through direct C–H arylation method, to synthesize the trithiazolylpyridine intermediate (Figure 1). The latter was then transformed to heterocycle core of GE2270 by adding a final bromination/Hantzsch sequence to build the last 2,4

• reported protocol of direct C–H arylation of tert-butyl thiazole-4-carboxylate (2) with 5-bromopicolinate ester 1 [21] could be scaled-up from milligram to multigram scale. The subsequent access to the 6-chloro-5-thiazolylpicolinate ester 4 was then achieved in good yields by following our previously

Copper-catalyzed asymmetric sp³ C–H arylation of tetrahydroisoquinoline mediated by a visible light photoredox catalyst

• Pierre Querard,
• Inna Perepichka,
• Eli Zysman-Colman and
• Chao-Jun Li

Beilstein J. Org. Chem. 2016, 12, 2636–2643, doi:10.3762/bjoc.12.260

• , St Andrews, Fife, KY16 9ST, UK 10.3762/bjoc.12.260 Abstract This report describes a highly enantioselective oxidative sp3 C–H arylation of N-aryltetrahydroisoquinolines (THIQs) through a dual catalysis platform. The combination of the photoredox catalyst, [Ir(ppy)2(dtbbpy)]PF6, and chiral copper

• catalysts provide a mild and highly effective sp3 C–H asymmetric arylation of THIQs. Keywords: C–H arylation; copper catalyst; enantioselectivity; visible light; Introduction Functionalization of sp3 C–H bonds is a unique and powerful transformation in modern organic synthesis, which remains a challenging

• developed the first direct sp3 C–H arylation of THIQ with arylboronic acids using a copper catalyst (Scheme 1) [30]. Oxygen gas and tert-butyl hydroperoxide (TBHP) were used as external oxidants, which gave moderate to good isolated yields (up to 75%). In addition, we demonstrated the first enantioselective

One-pot synthesis of 4′-alkyl-4-cyanobiaryls on the basis of the terephthalonitrile dianion and neutral aromatic nitrile cross-coupling

• Roman Yu. Peshkov,
• Elena V. Panteleeva,
• Wang Chunyan,
• Evgeny V. Tretyakov and
• Vitalij D. Shteingarts

Beilstein J. Org. Chem. 2016, 12, 1577–1584, doi:10.3762/bjoc.12.153

• introduction of an organometallic group is necessary. The last disadvantage is overcome to some extent by the direct C–H arylation protocols [18], but usually they are catalytic and thus the resulting cross-coupling products contain traces of transition metals difficult to remove that limits their use in areas

• such as pharmacy [22]. Because of the above-mentioned shortcomings of cross-coupling methods, we applied the method based on the direct C–H arylation of unactivated monocyanoarene 2 by the terephthalonitrile (12−) dianion [23]. It was shown that the interaction of 12− alkali metal salt with

Palladium-catalyzed picolinamide-directed iodination of remote ortho-C−H bonds of arenes: Synthesis of tetrahydroquinolines

• William A. Nack,
• Xinmou Wang,
• Bo Wang,
• Gang He and
• Gong Chen

Beilstein J. Org. Chem. 2016, 12, 1243–1249, doi:10.3762/bjoc.12.119

• cyclized under our previously reported Cu-catalyzed conditions to give PA-coupled THQ products with various substitution patterns in good yields (Scheme 2) [8]. As shown in Scheme 2, Pd-catalyzed PA-directed ε-C−H iodination can be used in concert with PA-directed γ-C−H arylation, PA-directed SEAr

• to our previously reported PA-directed SEAr approach. This Pd-catalyzed PA-directed ε-C−H iodination can be used in concert with the PA-directed γ-C−H arylation, PA-directed SEAr iodination, undirected SEAr iodination, and Cu-catalyzed C−N cyclization to quickly access tetrahydroquinolines bearing

• 5-iodo-THQ 27. PA-THQ 8 was susceptible to iodination at two positions. Under undirected SEAr conditions, 6-iodo-THQ 28 was produced in excellent yield and regioselectivity. Alternatively, a Pd-catalyzed C–H iodination reaction of 8 was developed which provides 8-iodo-THQ 29. Pd-catalyzed C−H

Synthesis of β-arylated alkylamides via Pd-catalyzed one-pot installation of a directing group and C(sp³)–H arylation

• Yunyun Liu,
• Yi Zhang,
• Xiaoji Cao and
• Jie-Ping Wan

Beilstein J. Org. Chem. 2016, 12, 1122–1126, doi:10.3762/bjoc.12.108

• accessed. Keywords: alkylamides; C–H arylation; directing group; in situ installation; one-pot; Introduction The elaboration of inert C–H bonds is regarded as the longstanding aim of modern organic synthesis. Upon the extensive efforts during the past decades, the exploration and application of C–H

• reactions with AQ and aryl iodides, the in situ generated propionamide intermedidates underwent selectively double β-C–H arylation to provide the corresponding 3,3-diarylamides 5 (Scheme 1). What’s more, when cyclohexylformic acid (2f) was subjected with AQ and aryl iodides, the C–H bonds at the two

• identical β-carbon atoms were simultaneously arylated to yield 2,6-diarylcyclohexylformamides 6 (Scheme 2). The results in the production of all these single and double arylated products indicated the broad application scope of the present one-pot C–H arylation approach in the synthesis of diverse

Cationic Pd(II)-catalyzed C–H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies

• Takashi Nishikata,
• Alexander R. Abela,
• Shenlin Huang and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2016, 12, 1040–1064, doi:10.3762/bjoc.12.99

• AgBF4 was used in place of AgOAc under optimized conditions for C–H arylation with aryl iodides, HBF4 (or any other added acid) was unnecessary for the catalytic reaction to occur. Here, since AgBF4 apparently reacts with I–Pd+BF4− to produce catalytically active Pd2+(BF4)2− (Scheme 22), and there are

• combinations, potentially applicable to other group 10 metals, and Ni in particular, may well offer related synthetic opportunities. Road map to enhanced C–H activation reactivity. C–H arylation results. Conditions A: Conducted at rt for 20 h in 2 wt % Brij 35/water (1 mL) with 10 mol % Pd(OAc)2, AgOAc (2

• reactions. Stoichiometric C–H arylation of iodobenzene. aYields based on Pd. Impact of acetate on the cationicity of Pd. Roles of additives in C–H arylation. Cross-coupling in the presence of AgBF4. A proposed catalytic cycle for Fujiwara–Moritani reactions. Proposed catalytic cycle of C–H activation/Suzuki

Gold-catalyzed direct alkynylation of tryptophan in peptides using TIPS-EBX

• Gergely L. Tolnai,
• Jonathan P. Brand and
• Jerome Waser

Beilstein J. Org. Chem. 2016, 12, 745–749, doi:10.3762/bjoc.12.74

• . It has been achieved in the past for example by Francis and co-workers and Ball and co-workers using rhodium-catalyzed carbene-insertion reactions [21][22][23] or via direct C–H arylation [24][25][26][27][28][29]. If the installation of alkynes on peptides or proteins is desired, an indirect method

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• -throughput and automated workflow platform, they have discovered a photoredox-catalyzed C–H arylation of N-arylamines with 1,4-dicyanobenzene (88) to produce pharmaceutically important benzylic amines. This reaction works well with piperazine substrate 87 to synthesize the α-arylated piperazine 89 in 95

Pyridylidene ligand facilitates gold-catalyzed oxidative C–H arylation of heterocycles

• Kazuhiro Hata,
• Hideto Ito,
• Yasutomo Segawa and
• Kenichiro Itami

Beilstein J. Org. Chem. 2015, 11, 2737–2746, doi:10.3762/bjoc.11.295

• University, Chikusa, Nagoya 464-8602, Japan 10.3762/bjoc.11.295 Abstract Triaryl-2-pyridylidene effectively facilitates the gold-catalyzed oxidative C–H arylation of heteroarenes with arylsilanes as a unique electron-donating ligand on gold. The employment of the 2-pyridylidene ligand, which is one of the

• strongest electron-donating N-heterocyclic carbenes, resulted in the rate acceleration of the C–H arylation reaction of heterocycles over conventional ligands such as triphenylphosphine and a classical N-heterocyclic carbene. In situ observation and isolation of the 2-pyridylidene-gold(III) species, as well

• elegant works of Lloyd-Jones and Russell on gold-catalyzed oxidative C–H arylation of simple arenes with arylsilanes have led the way to novel gold-catalyzed reactions that could not be achieved with other transition metals [68][69]. In these reactions, the oxidation of gold(I) to gold(III) is thought to

Efficient synthesis of π-conjugated molecules incorporating fluorinated phenylene units through palladium-catalyzed iterative C(sp²)–H bond arylations

• Fatiha Abdelmalek,
• Fazia Derridj,
• Safia Djebbar,
• Jean-François Soulé and
• Henri Doucet

Beilstein J. Org. Chem. 2015, 11, 2012–2020, doi:10.3762/bjoc.11.218

• -bromopyridine as coupling partners, a C–H arylation on the trifluorobenzene moiety of 14 did not proceed. We surveyed next the reactivity of 3-(2,3,4-trifluorophenyl)thiophene derivatives 5 and 6 in palladium catalyzed direct arylation using the same reaction conditions (Scheme 4). As expected, with 2-pentyl-4

Tuning the size of a redox-active tetrathiafulvalene-based self-assembled ring

• Sébastien Bivaud,
• Sébastien Goeb,
• Vincent Croué,
• Magali Allain,
• Flavia Pop and
• Marc Sallé

Beilstein J. Org. Chem. 2015, 11, 966–971, doi:10.3762/bjoc.11.108

• modulating the bulkiness of the ancillary group on the metal complex precursor. The tetrapyridyl-exTTF ligand L1 (Scheme 1, Figure 1a) was synthesized through a palladium catalysed C–H arylation from the naked exTTF [39]. We already reported that the self-assembly process of this tetratopic ligand with cis-M

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• -arylation. The following conventional cross-coupling or directed C–H arylation resulted in substituted phenanthridines. Homolytic aromatic substitution (HAS) by an aryl radical was used for the construction of biaryl motifs as alternative to transition metal-catalysed C–H bond arylation. That approach was

• . Trying to omit the expensive metal catalysts, several successful attempts of a transition metal-free approach for phenanthridine synthesis were reported. For instance application of a simple diol combined with KOt-Bu resulted in intramolecular C–H arylation to give the respective phenanthridine

Exploration of C–H and N–H-bond functionalization towards 1-(1,2-diarylindol-3-yl)tetrahydroisoquinolines

• Michael Ghobrial,
• Marko D. Mihovilovic and
• Michael Schnürch

Beilstein J. Org. Chem. 2014, 10, 2186–2199, doi:10.3762/bjoc.10.226

• immediately. Although a broad range of (hetero)arenes undergo C–H-arylation under copper catalysis, heterocycles possessing acidic N–H bonds react at the nitrogen preferentially [52][53]. Moreover, directing groups such as acetyl (in combination with a hypervalent iodine aryl source) [42], or 2-pyridinyl

Synthesis of phenanthridines via palladium-catalyzed picolinamide-directed sequential C–H functionalization

• Ryan Pearson,
• Shuyu Zhang,
• Gang He,
• Nicola Edwards and
• Gong Chen

Beilstein J. Org. Chem. 2013, 9, 891–899, doi:10.3762/bjoc.9.102

• . Extension of the cyclization–oxidation step to other arylated picolinamide substrates. The coupled cyclization–oxidation step detailed above was then used to synthesize phenanthridines from other arylated picolinamide substrates (Figure 2). In general, electron-rich arene motifs, installed by C–H arylation

• from easily accessible benzylamine picolinamides and aryl iodides. In the first step, an improved protocol allows us to carry out the Pd-catalyzed PA-directed C–H arylation reaction without the use of expensive silver additives. In the second step, application of PhI(OAc)2 and Cu(OAc)2 oxidant under

• were operated on a Waters LCT Premier instrument. Standard procedure for the Pd-catalyzed ortho C–H arylation reaction: A mixture of picolinamide 1 [30] (48 mg, 0.2 mmol, 1 equiv), aryl iodide 2 (94 mg, 0.4 mmol, 2 equiv), Pd(OAc)2 (2.2 mg, 0.01 mmol, 0.05 equiv), KHCO3 (40 mg, 0.4 mmol, 2.0 equiv

Copper-catalyzed CuAAC/intramolecular C–H arylation sequence: Synthesis of annulated 1,2,3-triazoles

• Rajkumar Jeyachandran,
• Harish Kumar Potukuchi and
• Lutz Ackermann

Beilstein J. Org. Chem. 2012, 8, 1771–1777, doi:10.3762/bjoc.8.202

• catalyst for two mechanistically distinct transformations for the synthesis of fully substituted annulated 1,2,3-triazoles as well as for twofold N–H/C–H bond arylations. Notable features of our strategy include (i) the development of a chemoselective C–H arylation-based three-component reaction, as well

• chromatography on silica gel (n-hexane/EtOAc). Copper-catalyzed step-economical C–H arylation-based cascade reaction. Copper-catalyzed sequential catalysis with alkyne 1a. Copper-catalyzed reaction sequence using alkyl bromides 2. General reaction conditions: 1 (1.00 mmol), 2 (1.00 mmol), NaN3 (1.05 mmol), CuI

Recent advances in direct C–H arylation: Methodology, selectivity and mechanism in oxazole series

• Cécile Verrier,
• Pierrik Lassalas,
• Laure Théveau,
• Guy Quéguiner,
• François Trécourt,
• Francis Marsais and
• Christophe Hoarau

Beilstein J. Org. Chem. 2011, 7, 1584–1601, doi:10.3762/bjoc.7.187

Convenient methods for preparing π-conjugated linkers as building blocks for modular chemistry

• Jiří Kulhánek,
• Filip Bureš and
• Miroslav Ludwig

Beilstein J. Org. Chem. 2009, 5, No. 11, doi:10.3762/bjoc.5.11

• ] proved to be infeasible. However, in light of the report by Itami and Yoshida [34], we attempted the Mizoroki–Heck C–H arylation of 4-bromo-N,N-dimethylaniline with an equimolar amount of vinylboronate pinacol ester leading to the desired 3c in 73% yield (Scheme 1, Method A). 4-Substituted 4

Synthesis of dihydrophenanthridines by a sequence of Ugi-4CR and palladium- catalyzed intramolecular C-H functionalization

• Florence Bonnaterre,
• Michèle Bois-Choussy and
• Jieping Zhu

Beilstein J. Org. Chem. 2008, 4, No. 10, doi:10.3762/bjoc.4.10

• ], the reaction of 3c with o-iodobenzaldehyde (2a), tert-butyl isocyanide (4a) and butyric acid (5a) or N-(tert-butoxycarbonyl)glycine (5c) afforded the corresponding Ugi adducts 6c and 6f in yields of 31% and 51%, respectively (entries 3, 6). The intramolecular C-H arylation process was found to be