Cobalt-catalyzed directed C–H alkenylation of pivalophenone N–H imine with alkenyl phosphates

• Wengang Xu and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2018, 14, 709–715, doi:10.3762/bjoc.14.60

• demonstrated that the combination of a cobalt–N-heterocyclic carbene (NHC) catalyst and a Grignard reagent allows for the arene C–H functionalization with organic halides and pseudohalides under the assistance of nitrogen directing groups [17][22][23][24][25][26][27]. In this connection, Ackermann developed a

• cycle illustrated in Scheme 5. An alkylcobalt species A, generated from the cobalt precatalyst and the Grignard reagent, would undergo cyclometalation of magnesium alkylidene amide 1·MgX, generated from imine 1 and the Grignard reagent, to give a cobaltacycle species B while liberating an alkane R–H

• Grignard reagent would furnish the alkenylation product 3·MgX and regenerate the species A. While the relationship between the ligand and the catalytic activity remains unclear, we speculate that a strong σ-donating ability of NHC ligands would facilitate the SET step among others. Conclusion In summary

Gram-scale preparation of negative-type liquid crystals with a CF₂CF₂-carbocycle unit via an improved short-step synthetic protocol

• Tatsuya Kumon,
• Shohei Hashishita,
• Takumi Kida,
• Shigeyuki Yamada,
• Takashi Ishihara and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 148–154, doi:10.3762/bjoc.14.10

• . The latter could be constructed through ring-closing metathesis of the corresponding precursor, e.g., 4,4,5,5-tetrafluoroocta-1,7-diene 5, using a Grubbs' catalyst. The octa-1,7-diene 5 could be obtained through a nucleophilic addition of a vinylic Grignard reagent to the γ-keto ester 6. Lastly, the γ

• , Scheme 2) and the results are summarized in Table 1. Thus, the treatment of 1.0 equiv of 7 with 2.0 equiv of 4-n-PrC6H4MgBr in THF at −78 °C overnight gave the corresponding γ-keto ester 6a in 85% isolated yield. Interestingly, although using an excess amount of Grignard reagent in this reaction, no

• adducts by over-reactions, e.g., A, B, C, etc. (Figure 2a), were observed. The suppression of the formation of the over-reacted products A–C may be brought about by the following possible reaction pathway (Figure 2b): (i) the nucleophilic attack of the Grignard reagent on the ester carbonyl functionality

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• O-deprotection, N-Fmoc-protection and oxidation to the carboxylic acid afforded the final Fmoc-Ala-ψ[(Z)-CF=CH]-Gly (49). Then, it was discovered that the diastereoselectivity of the addition of the Grignard reagent on 47 was enhanced when dimethylzinc (Me2Zn) was used as an additive (Table 1) [39

• Grignard reagent to give 105. The last three steps (simultaneous deprotection of the amine and the alcohol in acidic conditions, Fmoc protection of the amine and oxidation of the alcohol into the corresponding carboxylic acid) led to the formation of three isosteres: Fmoc-Val-ψ[(E)-CF=C]-Pro (106a), Fmoc

Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation

• Raja Ben Othman,
• Mickaël J. Fer,
• Laurent Le Corre,
• Sandrine Calvet-Vitale and
• Christine Gravier-Pelletier

Beilstein J. Org. Chem. 2017, 13, 1533–1541, doi:10.3762/bjoc.13.153

• organometallic reagents onto nucleoside aldehyde (Table 1), we decided to investigate the influence of the protecting groups of the uridine aldehyde on the stereochemical outcome of the nucleophilic addition of a Grignard reagent and we wish to report herein the results of our study. Results and Discussion We

• uracil (Table 2, entry 8) did not significantly change the 5’R/5’S ratio. In both cases, using 3.5 equivalents of Grignard reagent was required to complete the reaction. In order to improve this reverse diastereoselectivity, we envisaged the use of a more bulky protecting group, such as the

• diminished the yield to 55%. The bulkiness of the TIPS groups required the use of 5 equivalents of Grignard reagent to get a clean reaction and complete conversion of the starting material (Table 2, entry 14). The protection of the N-3 nitrogen with an allyl group was unfavorable and led to a 5’R/5’S 10:90

Phenylsilane as an effective desulfinylation reagent

• Wanda H. Midura,
• Aneta Rzewnicka and
• Jerzy A. Krysiak

Beilstein J. Org. Chem. 2017, 13, 1513–1517, doi:10.3762/bjoc.13.150

• 4 under conditions used by us before, i.e., by treatment with isopropylmagnesium chloride, gave a mixture of diastereomers 7a and 7b. It was probably due to epimerization on carbon C2 of the carbanion, formed after attack of the Grignard reagent on sulfur. To our satisfaction, utilization of the

Base-promoted isomerization of CF₃-containing allylic alcohols to the corresponding saturated ketones under metal-free conditions

• Yoko Hamada,
• Tomoko Kawasaki-Takasuka and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2017, 13, 1507–1512, doi:10.3762/bjoc.13.149

• -less expensive DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), whose results are reported in this article in detail. Results and Discussion Preparation of substrates (E)-6 was carried out by way of our recently reported one-pot procedure [16]: thus, after reaction of an appropriate Grignard reagent and ethyl

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

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• receptor modulator, 3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1’-indane]-5,5’-diol hydrochloride (216) which may be used for a new treatment of hot flush [88]. In this synthesis, the reaction of 5-methoxyindan-1-one (212) with the Grignard reagent 217 followed by acid-catalyzed dehydration and

NMR reaction monitoring in flow synthesis

• M. Victoria Gomez and
• Antonio de la Hoz

Beilstein J. Org. Chem. 2017, 13, 285–300, doi:10.3762/bjoc.13.31

• first case, the amount of oxidized Grignard reagent was significantly lower, showing the advantages of in-line measurements. In the in-line experiment the reaction mixture was introduced into the flow NMR cell at 1 mL min−1 showing a conversion of about 80% in 70 min. In this regard, Foley et al. [42

The reductive decyanation reaction: an overview and recent developments

• Jean-Marc R. Mattalia

Beilstein J. Org. Chem. 2017, 13, 267–284, doi:10.3762/bjoc.13.30

• method A (61) but aliphatic nitriles are not converted to the desired product with method B. Trapping of radicals with method A led the authors to propose the electron transfer mechanism described in Scheme 21. The complex 62 reacts with the Grignard reagent to form the nickel-magnesium hydride

Synthesis of polyhydroxylated decalins via two consecutive one-pot reactions: 1,4-addition/aldol reaction followed by RCM/syn-dihydroxylation

• Michał Malik and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2016, 12, 2602–2608, doi:10.3762/bjoc.12.255

• -addition of vinyl-MgBr followed by an aldol reaction (Scheme 6). The addition of a Grignard reagent to 17 was performed in THF at −45 °C in the presence of CuBr∙Me2S (0.5 equiv). After 15 min, a solution of aldehyde (either (R)- or (S)-10) in THF was added; the reaction mixture was warmed to −20 °C, and

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