Synthesis of 2-substituted tetraphenylenes via transition-metal-catalyzed derivatization of tetraphenylene

• Shulei Pan,
• Hang Jiang,
• Yanghui Zhang,
• Yu Zhang and
• Dushen Chen

Beilstein J. Org. Chem. 2016, 12, 1302–1308, doi:10.3762/bjoc.12.122

• synthesis of tetraphenylene in 1943 [22], in which 2,2’-dibromobiphenyl was converted to its corresponding Grignard reagent and subsequent addition of copper(II) chloride provided 1 in 16% yield, a variety of methods for constructing the tetraphenylene skeleton have been developed [23][24][25][26][27][28

NeoPHOX – a structurally tunable ligand system for asymmetric catalysis

• Jaroslav Padevět,
• Marcus G. Schrems,
• Robin Scheil and
• Andreas Pfaltz

Beilstein J. Org. Chem. 2016, 12, 1185–1195, doi:10.3762/bjoc.12.114

• threonine derivative 12 (Scheme 4), led to an unidentified mixture of products. Surprisingly, when the Grignard reagent was added at 0 °C instead of −78 °C and reaction mixture subsequently warmed up to room temperature, the desired product 19 was formed in 78% yield. After having resolved these issues, the

Modular synthesis of the pyrimidine core of the manzacidins by divergent Tsuji–Trost coupling

• Sebastian Bretzke,
• Stephan Scheeff,
• Felicitas Vollmeyer,
• Friederike Eberhagen,
• Frank Rominger and
• Dirk Menche

Beilstein J. Org. Chem. 2016, 12, 1111–1121, doi:10.3762/bjoc.12.107

• alkaloids of marine origin. Additional features of this route include the stereoselective generation of the central amine core with an appending quaternary center by an asymmetric addition of a Grignard reagent to a chiral tert-butanesulfinyl ketimine following an optimized Ellman protocol and a cross

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• diastereoselectively converted with a Grignard reagent into the amine 53 as a key step of the synthesis [78]. Cbz protection followed by ozonolysis with subsequent reductive amination and hydrogenolysis led to the 1,3-diamine 54. The cyclisation to the guanidine functionality was achieved with the novel

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

• Thibault E. Schmid,
• Sammy Drissi-Amraoui,
• Christophe Crévisy,
• Olivier Baslé and
• Marc Mauduit

Beilstein J. Org. Chem. 2015, 11, 2418–2434, doi:10.3762/bjoc.11.263

• the presence of a substoichiometric amount of copper chloride. Ten years later, Alexakis and Posner described the addition of a vinyl Grignard reagent to the conjugated dienone 14, affording product 15 in 66% yield, ultimately leading to pseudoguaiane [15]. The initial results regarding stoichiometric

• outcome of the ACA reaction with α,β,δ,γ-unsaturated ketones [18]. Using a Grignard reagent as the nucleophile, it appeared that catalytic systems based on phosphoramidite ligands favored the formation of the 1,6-adduct. However, the use of catalytic systems based on an hydroxyalkyl NHC ligand (Cu(OTf)2

• and a conjugate addition of a Grignard reagent to the newly formed exocyclic double bound were subsequently performed. Overall, this four-step process afforded the sterically congested cyclohexanone 72 in a 30% overall yield, with a dr of 2:1 and 96% ee (Scheme 20). In 2012, Alexakis and Gremaud

Total synthesis of panicein A₂

• Lili Yeung,
• Lisa I. Pilkington,
• Melissa M. Cadelis,
• Brent R. Copp and
• David Barker

Beilstein J. Org. Chem. 2015, 11, 1991–1996, doi:10.3762/bjoc.11.215

• ). Altering the solvent system to a 1:1 mixture of THF and diethyl ether, which also improved the solubility of the Grignard reagent, increased the yield of 9 to 95%. With alcohol 9 in hand, the next step was the key coupling of alcohol 9 and phenol 16 [11] to form the required propargyl ether 8. Godfrey et

Copper-catalyzed aerobic radical C–C bond cleavage of N–H ketimines

• Ya Lin Tnay,
• Gim Yean Ang and
• Shunsuke Chiba

Beilstein J. Org. Chem. 2015, 11, 1933–1943, doi:10.3762/bjoc.11.209

• , the cyano group of carbonitrile 1a is transferred to Grignard reagent 2a to afford p-tolunitrile (5a). Considering the importance of carbonitriles in organic synthesis [56], we postulated that the cyano group transfer from simple carbonitriles onto Grignard reagents could be realized using this

• current transformation toward the synthesis of oxaspirocyclohexadienones 3. Therefore, the reactions of carbonitriles 1b–d were examined under the current best reaction conditions (Table 1, entry 8) using p-tolyl Grignard reagent 2a (Table 2). Carbonitrile 1b, having methyl groups in ortho-positions on

• 63% yield. The present method could also be applied for the cyanation of the primary alkyl Grignard reagent, phenethylmagnesium bromide (for 5j), albeit the product yield was moderate. Conclusion In summary, we have demonstrated a copper-catalyzed aerobic generation of iminyl radicals from the

Design and synthesis of hybrid cyclophanes containing thiophene and indole units via Grignard reaction, Fischer indolization and ring-closing metathesis as key steps

• Sambasivarao Kotha,
• Ajay Kumar Chinnam and
• Mukesh E. Shirbhate

Beilstein J. Org. Chem. 2015, 11, 1514–1519, doi:10.3762/bjoc.11.165

• started with a Grignard addition reaction. In this context, commercially available thiophene-2,5-dicarbaldehyde (4) was reacted with the Grignard reagent [23] derived from 5-bromo-1-pentene to give diol 6 as a diastereomeric mixture (Scheme 1). Alternatively, the dialdehyde 4 can be prepared by using the

Spiro annulation of cage polycycles via Grignard reaction and ring-closing metathesis as key steps

• Sambasivarao Kotha,
• Mohammad Saifuddin,
• Rashid Ali and
• Gaddamedi Sreevani

Beilstein J. Org. Chem. 2015, 11, 1367–1372, doi:10.3762/bjoc.11.147

• , we found that the addition of the etheral solution of the hexacyclic dione 10 to a freshly prepared allyl Grignard reagent at 0 °C gave the expected diallylated compound 11 in 88% yield (Scheme 3). The Grignard reagent at higher concentration (1.0 M solution) exists as a mixture of dimer, trimer and

• polymeric components. However, the home-made Grignard reagent at low concentration (0.1 M solution) exists mostly in the monomeric form. So, we speculate that the difference in the concentration may be responsible for the formation of diol 11 [49][50][51]. Alternatively, when the diketone was reacted with

• an excess amount of Grignard reagent, the carbonyl groups are attacked simultaneously by the Grignard reagent and resulted in the formation of diol 11. When an excess amount of substrate containing carbonyl group was reacted with a limited amount of Grignard reagent, the oxyanion formed by the

Synthesis of γ-hydroxypropyl P-chirogenic (±)-phosphorus oxide derivatives by regioselective ring-opening of oxaphospholane 2-oxide precursors

• Iris Binyamin,
• Shoval Meidan-Shani and
• Nissan Ashkenazi

Beilstein J. Org. Chem. 2015, 11, 1332–1339, doi:10.3762/bjoc.11.143

• may possess further functionalities in addition to the phosphorus center such as the γ-hydroxypropyl group which results from the ring opening and π-donor moieties such as aryl, allyl, propargyl and allene which originates from the Grignard reagent. Keywords: chirogenic phosphorus; Grignard reagents

• reagents such as aliphatic (Me, Et), aromatic (Ph), cyclic (cyclopentyl) or allylic derivativess (Table 1). The products were identified by multinuclear NMR and MS (CI) detection. Generally, the reaction was performed in cooled (0 ºC) ether, using 3 equiv of the Grignard reagent, while warming to rt with

• as one equiv led to an incomplete reaction, while more than 3 equiv of the Grignard reagent led to dialkylation of the phosphorus atom, and formation of phosphine oxide side products. This phenomenon was most noticeable using phenylmagnesium bromide as a nucleophile: 2 equiv of the reagent were

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• Grignard reagent 71 in the presence of a nickel phosphine complex 72 gave muscopyridine 73 in a single step (Scheme 11). This strategy has been applied to generate a variety of pyridinophanes by varying the chain length of the Grignard reagent. McMurry coupling: Kuroda and co-workers [99] have reported the

• diol 183 gave [1.1.6]metaparacyclophane derivative 184 (Scheme 29). Using the same approach, a butenyl Grignard reagent was added to compound 181 to generate diol 185. Surprisingly, after the addition of G-II catalyst 13, the two RCM products 186 and 189 were obtained [135]. The outcome of product 189

• provided acrylate 226, which was subjected to enantioselective copper-catalyzed conjugate addition with a methyl Grignard reagent involving (R)-tol-BINAP ligand to generate ester 227 in good yield and high enantiopurity. This intermediate was then converted to the key metathesis precursor involving a three

Development of variously functionalized nitrile oxides

• Haruyasu Asahara,
• Keita Arikiyo and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2015, 11, 1241–1245, doi:10.3762/bjoc.11.138

• , amides, aldehyde, and ketone upon treatment with hydroxide, alkoxide, amine, diisobutylaluminium hydride and Grignard reagent, respectively. In these transformations, N-methyl-N-tosylcarboxamides behave like a Weinreb amide. Similarly, N-methyl-5-phenylisoxazole-3-carboxamide was converted into 3

• were not detected (Table 2, entries 13 and 14). In the case of an aromatic Grignard reagent, the undesired reaction was suppressed. Although the reaction did not occur at −78 °C, the substitution proceeded successfully at −40 °C, affording ketones 9i and 10i (Table 2, entries 15 and 16). Sodium

• -methylcarbamoyl group to an acyl or formyl group was achieved upon treatment with a Grignard reagent or with DIBAL (Table 3, entries 7 and 8). The chemical conversion of N-methylamides to versatile carbonyl functions was systematically studied. In this protocol, the tosyl group was found to be effective for the

Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

• Mathieu L. Lepage,
• Antoine Mirloup,
• Manon Ripoll,
• Fabien Stauffert,
• Anne Bodlenner,
• Raymond Ziessel and
• Philippe Compain

Beilstein J. Org. Chem. 2015, 11, 659–667, doi:10.3762/bjoc.11.74

• reaction positions 2 and 6 of the BODIPY [60]. Substitution of both fluoro groups on the boron was realized using the Grignard reagent of 1-[2”’-(2”-{2’-(2-methoxyethoxy)ethoxy}ethoxy)ethoxy]prop-2-yne [61] and the BODIPY derivative 8. With these precursors in hands it was easy to transform the iodo

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• was done by Mukaiyama and Iwasawa in 1981 [28]. DCA reactions were performed on a series of α,β-unsaturated amides, which employed L-ephedrine as a chiral auxiliary (Scheme 2). Mechanistically, it was supposed that the Grignard reagent formed an internal chelate between the nitrogen and the oxygen on

• the auxiliary that locked the conformation of the molecule. The excess Grignard reagent would add to the double bond from the less sterically hindered side, thus leading to the diastereoselectivity. Note that when using Grignard reagents as nucleophiles in CA reactions, the possibility of the 1,2

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

Palladium-catalysed cyclisation of alkenols: Synthesis of oxaheterocycles as core intermediates of natural compounds

• Miroslav Palík,
• Jozef Kožíšek,
• Peter Koóš and
• Tibor Gracza

Beilstein J. Org. Chem. 2014, 10, 2077–2086, doi:10.3762/bjoc.10.216

• reaction with the corresponding Grignard reagent in the presence of CeCl3·2LiCl providing diols 33–35 in good overall yields and high diastereoselectivity (d.r. >20:1). Additionally, allylic acetate 37 was obtained starting from 33 in a seven-step sequence in 30% overall yield. The acetonisation of hydroxy

Reaction of selected carbohydrate aldehydes with benzylmagnesium halides: benzyl versus o-tolyl rearrangement

• Maroš Bella,
• Bohumil Steiner,
• Vratislav Langer and
• Miroslav Koóš

Beilstein J. Org. Chem. 2014, 10, 1942–1950, doi:10.3762/bjoc.10.202

• the typical Grignard reaction where the Grignard reagent is coupled with a carbonyl compound. Moreover, the anomeric position was involved in the reaction and there was an important limitation: the formation of the unexpected o-tolyl rearrangement product entailed the participation of both of the

• solution of Grignard reagent 2 into a solution of the carbohydrate aldehyde 3 (i.e., reverse addition of reactants) in the mole ratio of 1.3:1 had some positive effect in respect of the yield (but not of the proportion of isomers) of the Grignard reaction products, we applied these parameters in subsequent

• unambiguously confirmed by single-crystal X-ray analysis. The formation of o-tolyl isomers 4 and 5 can be explained by the possible reaction sequence (path 1) depicted in Scheme 2. The first step involves an addition of the Grignard reagent to the saccharide aldehyde, producing a trienic magnesium alkoxide

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

• Grignard reagent which was reacted with 9-fluorenone to afford tertiary alcohol 4 in 55% yield. Adopting a protocol of Tour et al. [16] led to 2-methoxy-9,9'-spirobifluorene (5) in 95% yield via acidic condensation of 4. Next, the methoxy group was cleaved quantitatively by reaction with boron tribromide

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• substrates). In the next step, addition of a slight excess of the 3-chloropropanol-derived Grignard reagent 6 (final concentration 0.25–0.3 mol/L), which was found to be superior in the final concentration to the reported ClMgnPrOMgCl derivative (0.1–0.2 mol/L in our hands) [69], to amides 5a–d resulted in

• lactamisation of the ester function was observed as a side product in traces (<5%). Next, amidation of the acids 2e and 2f gave the amides 5e and 5f in good yields under standard coupling conditions. Unfortunately, the ketone 7e was obtained in only 24% yield through addition of the Grignard reagent 6 to amide

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• /oxidation, followed by Swern oxidation of the resulting alcohol to yield aldehyde 66. Addition of cyclopropyl-Grignard reagent 67 [67][68], followed by oxidation to the corresponding ketone yielded vinylcyclopropane 68. Deprotonation and TMS-protection furnished silyl-enolether 69, which underwent the

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• consisting of ozonolysis and reductive dehydroxylation provided the indolizidine derivative 5, which completed the formal enantioselective total synthesis of pumiliotoxins 251D and 237A. Keywords: enantioselective synthesis; Grignard reagent; pumiliotoxin 237A; pumiliotoxin 251D; reductive dehydroxylation

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

• substituted Grignard reagent 1.26. A Friedel–Crafts type acylation promoted by either triflic acid or polyphosphoric acid (PPA) furnishes the tricyclic structure 1.28 which upon N-demethylation affords clarinex (1.22). One of the top-selling classes of pharmaceuticals containing the pyridine ring are the

A reductive coupling strategy towards ripostatin A

• Kristin D. Schleicher and
• Timothy F. Jamison

Beilstein J. Org. Chem. 2013, 9, 1533–1550, doi:10.3762/bjoc.9.175

• reproducible yields than either the commercially available Grignard reagent or the organocerium. Johnson–Claisen rearrangement [50] of 44 proceeded smoothly to give the γ,δ-unsaturated ester 45. Conducting the reaction without added solvent in a microwave reactor at 170 °C allowed the reaction to proceed in

Controlled synthesis of poly(3-hexylthiophene) in continuous flow

• Helga Seyler,
• Jegadesan Subbiah,
• David J. Jones,
• Andrew B. Holmes and
• Wallace W. H. Wong

Beilstein J. Org. Chem. 2013, 9, 1492–1500, doi:10.3762/bjoc.9.170

• thiophene Grignard monomer 2 is prepared from the magnesium exchange reaction of an alkyl Grignard reagent and 2,5-dibromo-3-hexylthiophene (1, Scheme 1a). It should be noted here that a mixture of Grignard monomers 2a and 2b is produced in this step, typically in a ratio of 75:25. Only 2a participates in

• initiated with this complex showed lower defect levels [23][24]. After successfully experimenting with this catalyst in batch conditions, the reagent was applied in flow processing for the synthesis of P3HT (Scheme 1b). The thiophene Grignard reagent 2 was prepared by traditional batch chemistry and the

• concentration of the Grignard reagent 2 and the flow rates of the monomer and catalyst. The results for the flow polymerizations are summarized in Table 2, and Figure 3 shows the correlation between [M]0/[I]0 and molecular weight and comparison with batch experiments. The polymerization in flow compared well

Preparation and ring-opening reactions of N-diphenylphosphinyl vinyl aziridines

• Ashley N. Jarvis,
• Andrew B. McLaren,
• Helen M. I. Osborn and
• Joseph Sweeney

Beilstein J. Org. Chem. 2013, 9, 852–859, doi:10.3762/bjoc.9.98

• mixture. Aza-Darzens synthesis of an N-Dpp vinyl aziridine. Closed transition state delivers E-aziridines. Open transition state leading to (Z)-5. Ring opening by Grignard reagent. Aza-Darzens synthesis of N-Dpp vinyl aziridines. SN2′-Ring-opening of N-Dpp vinyl aziridines by organometallic reagents. Ring