Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• transformations include the carboxylation of a (trimethylsilylmethyl)cyclopropene in the presence of a fluoride promoter [22], and also the addition of electrophiles to (lithiomethyl)cyclopropenes generated by lithiation of the corresponding methylcyclopropenylsulfone [23] or -sulfoxide [24]. More recently, the

Silanediol versus chlorosilanol: hydrolyses and hydrogen-bonding catalyses with fenchole-based silanes

• Falco Fox,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2019, 15, 167–186, doi:10.3762/bjoc.15.17

• catalytic and anion binding characteristics. Results and Discussion Enantiopure dichlorosilane 7 is readily accessible by lithiation of BIFOL (5) [28][52][54][59] and subsequent reaction with tetrachlorosilane (92% yield, Scheme 2). Unlike the hydrolysis of BIFOP-Cl (6) to BIFOP-OH, the dichlorosilane 7 is

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• anion with the two hydroxy groups of the calixarene ligand to selectively direct the nucleophile towards one carbon atom of the π-allyl intermediate in the presence of potassium cations. In 2009 and 2010, Arnott et al. utilized a chiral isopropyloxazoline as an ortho-lithiation directing group in order

• to synthesize inherently chiral calixarenes 36 and 37 [43][44]. In a continuation of their previous studies, they have reported diastereoselective synthesis of inherently chiral calixarene derivatives 38 and 39 via chiral tert-butyloxazoline-directed lithiation (Figure 4) [45]. It has been shown that

• selectivity of ortho-lithiation could be tuned by changing the alkyllithium reagent employed. The performance of four inherently chiral bidentate calix[4]arene ligands in the asymmetric Tsuji–Trost allylation reaction (Scheme 10) has been evaluated and compared to that of the planar model ligands. Inherently

Nucleophilic fluoroalkylation/cyclization route to fluorinated phthalides

• Masanori Inaba,
• Tatsuya Sakai,
• Shun Shinada,
• Tsuyuka Sugiishi,
• Yuta Nishina,
• Norio Shibata and
• Hideki Amii

Beilstein J. Org. Chem. 2018, 14, 182–186, doi:10.3762/bjoc.14.12

• been few reports on the preparation of fluoroalkyl phthalides [11][12][13][14][15][16][17][18][19]. The first synthesis of 3-(trifluoromethyl)phthalides was accomplished by Reinecke and Chen in 1993. They studied ortho-lithiation of phenyloxazolines and the subsequent reactions with pentafluoroacetone

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• (prepared from O-benzyl-protected glucose and glutaric anhydride) was introduced at the free 6’-OH group using DCC and DMAP to give 22. The anomeric allyl group was cleaved by standard procedure, the phosphorylation of the 1-OH group was performed by 1-O-lithiation and subsequent treatment with tetrabenzyl

• regioselectively phosphorylated in a stereoselective manner by 1-O-lithiation with LHMDS, and subsequent treatment with tetrabenzyl pyrophosphate at −78 °C. Protecting groups were removed by hydrogenolysis on Pd-black to give H. pylori lipid A 39. For the synthesis of Kdo-lipid A 41 entailing a phosphoethanolamine

• -benzyloxyacyl and (R)-3-acyloxyacyl fatty acids furnished the lipid A precursor 50 (Scheme 6). Cleavage of the 1-O-allyl protecting group and stereoselective phosphorylation of the anomeric position via 1-O-lithiation with LHMDS, and subsequent treatment with tetrabenzyl pyrophosphate gave tetraacylated P

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

• the C1–C20 seco acid via formation of the C9–C10 bond by an epoxide-opening reaction with an alkyne-derived alkenyl trialkylaluminate. A distinct strategy was also chosen by the Aggarwal group, which connected the linear C1–C11 fragment to the C12–C20 fragment employing their lithiation–borylation

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

• ICZs [37], as well as C2- and C2,8-bromination of 6,12-disubstituted ICZs [23][38]. Bromo-containing ICZ derivatives have also been involved in further lithiation and metal-catalyzed cross-coupling reactions. Herein, we describe an effective protocol for nitration of 5,11-dihydroindolo[3,2-b]carbazoles

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• the mole ratio between ketone (obtained by Grignard’s addition) and lithiated compound (obtained by lithiation) is critical. At plant scale, in-line monitoring technique should be used to monitor the outlet concentration of both the reactions. A suitable ratio controller should be employed to control

• the conversion can be monitored online to check the variation around the set-point value. This process stream containing the ketone intermediate can be precooled to −50 °C. Aryl bromide and n-BuLi are precooled at −50 °C and reacted to obtain the lithiated product. The control strategy for lithiation

• synthesis will help to generate very valuable data that can be used for transforming this chemistry into a process. Lithiation reaction is highly exothermic and a special control strategy should be employed to avoid a runaway situation [44]. However, if a runaway event occurs an appropriate strategy should

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

• (pyridin-2-yl)-substituted derivatives 3a,b upon treatment with 1.1 equivalents of n-BuLi at −78 °C. Subsequent reaction with CO2 led to almost complete conversion to 4a,b as detected by TLC (Scheme 3). In contrast, with 3,5-di(pyridin-3-yl)-substituted derivatives 3c,d, the lithiation reaction was slower

• amounts of dehalogenation products observed. The reactions were carried out either using 2 equivalents of commercially available RZnBr or 3 equivalents of in-situ-prepared RZnCl (see Supporting Information File 1). Similarly as observed in the course of the lithiation/carboxylation reactions (Scheme 3

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

• polyfunctionalized biaryls, using a flow microreactor, has been recently reported by Yoshida [54]. Using the integrated microflow system reported in Scheme 8, arylboronic esters were prepared by a lithiation/borylation sequence, and used in a Suzuki–Miyaura coupling in a monolithic reactor. A remarkable aspect of

• -substituted pyridines. The regioselective lithiation of halopyridines with lithium diisopropylamide (LDA) was conducted under mild conditions on substrate 6 (Scheme 10). The addition of a little amount of THF was necessary in order to avoid clogging and the tendency of the lithiated intermediate to eliminate

• microreactor system. Control of anionic Fries rearrangement reactions by using submillisecond residence time. (Adapted with permission [43], copyright 2016 American Association for the Advancement of Science). Flow microreactor system for lithiation, borylation, Suzuki–Miyaura coupling and selected examples of

High performance p-type molecular electron donors for OPV applications via alkylthiophene catenation chromophore extension

• Paul B. Geraghty,
• Calvin Lee,
• Jegadesan Subbiah,
• Wallace W. H. Wong,
• James L. Banal,
• Mohammed A. Jameel,
• Trevor A. Smith and
• David J. Jones

Beilstein J. Org. Chem. 2016, 12, 2298–2314, doi:10.3762/bjoc.12.223

• : Our modified synthesis of BTR and its analogues starts with the lithiation of 3-alkylthiophene 1a–c by lithium diisopropylamide formed in situ from the reaction of n-butyllithium with diisopropylamine (DIA) in the presence of the alkylthiophene, followed by quenching with trimethylsilyl chloride to

A modular approach to neutral P,N-ligands: synthesis and coordination chemistry

• Vladislav Vasilenko,
• Torsten Roth,
• Clemens K. Blasius,
• Sebastian N. Intorp,
• Hubert Wadepohl and
• Lutz H. Gade

Beilstein J. Org. Chem. 2016, 12, 846–853, doi:10.3762/bjoc.12.83

• aromatic formamidines (1a–c) starting from triethyl orthoformate and aromatic amines. Low-temperature lithiation of 1 and addition to achiral (R = Ph) and axially chiral (R2 = BINOL) chlorophosphines R2PCl gave ligands 2 and 3 in excellent yields (Scheme 1) [11]. If the correct stoichiometry is maintained

Syntheses of dibenzo[d,d']benzo[2,1-b:3,4-b']difuran derivatives and their application to organic field-effect transistors

• Minh Anh Truong and
• Koji Nakano

Beilstein J. Org. Chem. 2016, 12, 805–812, doi:10.3762/bjoc.12.79

• are described in Scheme 1 and Scheme 2. 3-Decylanisole was first synthesized from commercially available 3-bromoanisole via iron-catalyzed cross-coupling reaction with decylmagnesium bromide in 71% yield [47]. Lithiation of the obtained 3-decylanisole with s-BuLi and the following treatment with 2

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

• pharmaceuticals. Herein we summarize the current synthetic methods available to perform C–H functionalization on piperazines in order to lend structural diversity to this privileged drug scaffold. Multiple approaches such as those involving α-lithiation trapping, transition-metal-catalyzed α-C–H

• : α-lithiation; C–H functionalization; heterocycle; photoredox catalysis; piperazine; Introduction Piperazine is one of the most important saturated N-heterocycles frequently found in life-saving small-molecule pharmaceuticals [1]. In a recent statistical study done by Njardarson and co-workers

• piperazines. Review Direct α-C–H lithiation trapping Since the seminal discovery made by Beak and Lee [28][29], α-functionalization of N-Boc-protected nitrogen heterocycles via direct α-C–H lithiation trapping has been a straightforward and effective method to introduce various substituents on the α-carbon

From steroids to aqueous supramolecular chemistry: an autobiographical career review

• Bruce C. Gibb

Beilstein J. Org. Chem. 2016, 12, 684–701, doi:10.3762/bjoc.12.69

• there are sixteen aromatic carbons (labeled endo-, exo- and exterior- in Scheme 7) that are doubly activated by O-substituents around the rim of the pocket. It transpires that lithiation does not occur at the exterior positions of these hosts, so there are only (!) eight positions where reaction occurs

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

• Hans Sterckx,
• Johan De Houwer,
• Carl Mensch,
• Wouter Herrebout,
• Kourosch Abbaspour Tehrani and
• Bert U. W. Maes

Beilstein J. Org. Chem. 2016, 12, 144–153, doi:10.3762/bjoc.12.16

• the World Health Organization essential medicines list and despite numerous side effects it remains one of the most effective antimalarial drugs on the market [37][38]. Its classical synthesis (Scheme 2, top) is based on the lithiation of 4-bromo-2,8-bis(trifluoromethyl)quinoline (7a) and quenching

Copper-catalyzed arylation of alkyl halides with arylaluminum reagents

• Bijay Shrestha and
• Ramesh Giri

Beilstein J. Org. Chem. 2015, 11, 2400–2407, doi:10.3762/bjoc.11.261

• added dropwise a solution of aryllithium (3.0 mmol, generated from the lithiation of aryl iodides with 1 equiv of n-BuLi in THF) at room temperature. After 45 minutes, the solvent was removed to obtain a triarylaluminum reagent containing 3 equivalents of LiCl, which was then dissolved in NMP (5 mL

C–H bond halogenation catalyzed or mediated by copper: an overview

• Wenyan Hao and
• Yunyun Liu

Beilstein J. Org. Chem. 2015, 11, 2132–2144, doi:10.3762/bjoc.11.230

• electron-enriched arenes [7][8][9], diazotization/halogenations of anilines [10], and ortho-lithiation/halogenations sequence [11] among others are widely used as traditional strategies for creating C–X bonds. However, one or more problems such as poor site-selectivity, reliance on toxic halogen sources

Polythiophene and oligothiophene systems modified by TTF electroactive units for organic electronics

• Alexander L. Kanibolotsky,
• Neil J. Findlay and
• Peter J. Skabara

Beilstein J. Org. Chem. 2015, 11, 1749–1766, doi:10.3762/bjoc.11.191

• the synthesis of 25c – a compound required for synthetic pathway B – was found to be repeated sequential lithiation of vinylene trithiocarbonate (26) [67] followed by subsequent trapping of the lithium organic species with thiophenecarboxaldehyde 27 [60]. The diol 25e, formed as a product of this

• tetrabutylammonium hexafluorophosphate as the supporting electrolyte. On a larger scale, chemical oxidation by FeCl3 in nitrobenzene was used which after purification, afforded 51 in a 24% yield. Lithiation of compound 28b with LDA and successive trapping of the aryllithium compound with perfluorohexyl iodide

Pyridine-promoted dediazoniation of aryldiazonium tetrafluoroborates: Application to the synthesis of SF₅-substituted phenylboronic esters and iodobenzenes

• George Iakobson,
• Junyi Du,
• Alexandra M. Z. Slawin and
• Petr Beier

Beilstein J. Org. Chem. 2015, 11, 1494–1502, doi:10.3762/bjoc.11.162

• literature describes the synthesis of 3- or 4-(pentafluorosulfanyl)phenylboronates or boronic acids from SF5-bromobenzenes via lithiation or magnesiation. These approaches suffer from low yields and other drawbacks [70][71]. For lithiation of the aryl bromide, t-BuLi had to be used and the formation of

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship

• Mohamed Yacine Ameur Messaoud,
• Ghenia Bentabed-Ababsa,
• Madani Hedidi,
• Aïcha Derdour,
• Floris Chevallier,
• Yury S. Halauko,
• Oleg A. Ivashkevich,
• Vadim E. Matulis,
• Laurent Picot,
• Valérie Thiéry,
• Thierry Roisnel,
• Vincent Dorcet and
• Florence Mongin

Beilstein J. Org. Chem. 2015, 11, 1475–1485, doi:10.3762/bjoc.11.160

• bromobenzene. However, when this ortho-bromine effect is combined with the meta-effect of a pyrrolyl group, the corresponding CH acidities are increased (see Figure 5), and things become different. Thus, whereas the direct deproto-lithiation of bromobenzene leads to highly unstable 2-bromophenyllithium, that

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• important pharmaceutical. The Kirschning group (2013) also demonstrated a multi-step flow synthesis of the antidepressant amitriptyline (127) [105]. They developed a sequence harnessing reactions at several different temperature regimes allowing processing of low temperature lithiation and carboxylation

Inherently chiral calix[4]arenes via oxazoline directed ortholithiation: synthesis and probe of chiral space

• Simon A. Herbert,
• Laura J. van Laeren,
• Dominic C. Castell and
• Gareth E. Arnott

Beilstein J. Org. Chem. 2014, 10, 2751–2755, doi:10.3762/bjoc.10.291

• Simon A. Herbert Laura J. van Laeren Dominic C. Castell Gareth E. Arnott Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa 10.3762/bjoc.10.291 Abstract The diastereoselective oxazoline-directed lithiation of calix[4]arenes is

• . A lower diastereoselectivity was also seen for higher reaction concentrations, which has been attributed to solubility and mixing problems. The excess of alkyllithium has been found to result in more convenient lithiation times (4–7 hours), although the tert-butyl calix[4]arenes typically required

• much longer lithiation times (24–48 h). In all cases the ligand N,N,N',N'-tetramethylethylenediamine (TMEDA) was crucial for success. Our first observation, when looking at the results in Table 1, was that although the starting materials may be considered structurally similar, there was no correlation

Microsolvation and sp²-stereoinversion of monomeric α-(2,6-di-tert-butylphenyl)vinyllithium as measured by NMR

• Rudolf Knorr,
• Monika Knittl and
• Eva C. Rossmann

Beilstein J. Org. Chem. 2014, 10, 2521–2530, doi:10.3762/bjoc.10.263

• charge at C-α of 4 (Scheme 2) into the α-aryl π-orbital system. The resulting negative lithiation NMR shifts Δδ = δ(4) − δ(8a) for 13C-4 and 4-H (entries 2 and 3, Table 1) point to a significant charge transfer [9][11] from C-α to C-4 of 4&3THF. The full set of Δδ values of 4 in the two THF solutions is

• charges in positions that are nearer than C-4 to the C–Li bond. Almost all lithiation shifts Δδ shown in 9c (Figure 1) for α-(2,4,6-tri-tert-butylphenyl)vinyllithium (10) in THF [15] are closely similar to those of 4 in 9a and 9b, even though the chemical shifts δ(C-4) of 4 and 10 (Tables S11 and S12, [15

• . Therefore, this σ-inductive “contamination” may be removed by subtraction, as described previously [18] for many other α-substituents: The differences Δ2JH,H = 2JH,H(4) − 2JH,H(8a) were measured in situ and are included in Table 1 so as to present “purified” lithiation-induced contributions to the 2JH,H

P(O)R₂-directed Pd-catalyzed C–H functionalization of biaryl derivatives to synthesize chiral phosphorous ligands

• Rong-Bin Hu,
• Hong-Li Wang,
• Hong-Yu Zhang,
• Heng Zhang,
• Yan-Na Ma and
• Shang-dong Yang

Beilstein J. Org. Chem. 2014, 10, 2071–2076, doi:10.3762/bjoc.10.215

• prefunctionalization or lithiation of substrate. However, these methods are not compatible for some activated functional groups in precursor compounds. Over the past several years, we have achieved reactions of C–P bond formation with new and efficient protocols via transition metal-catalysis [11][12][13][14][15][16