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

Regio- and stereoselective carbometallation reactions of N-alkynylamides and sulfonamides

• Yury Minko,
• Morgane Pasco,
• Helena Chechik and
• Ilan Marek

Beilstein J. Org. Chem. 2013, 9, 526–532, doi:10.3762/bjoc.9.57

• primary and secondary alkylcopper species (still obtained in diethyl ether from 1.0 equiv of a Grignard reagent and 1.0 equiv of CuBr, conditions A) to give the corresponding vinylcopper intermediate 5. Simple hydrolysis led to the enamide 6a,c in good isolated yields after purification by column

Highly stereocontrolled synthesis of trans-enediynes via carbocupration of fluoroalkylated diynes

• Tsutomu Konno,
• Misato Kishi and
• Takashi Ishihara

Beilstein J. Org. Chem. 2012, 8, 2207–2213, doi:10.3762/bjoc.8.249

• also examined the reaction with the cuprate prepared from Grignard reagent, n-BuMgBr. As summarised in Table 3, entries 3–5, a significant decrease of the yield was observed when the reaction was performed by using 1.2 equiv of cuprate. Very interestingly, the use of 1.5 equiv of the higher-ordered

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225

• Scheme 17). Starting with the simplest bisallene, the C6-isomer 1,2,4,5-hexatetraene (2), this parent system was first prepared by a protocol according to general route (ii) [6]. As summarized in Scheme 1, conversion of the C3-building block propargyl bromide (19) into its Grignard reagent, allenyl

• ), but the composition of the product mixture is anything but simple (Scheme 5) [32][33][34][35][36]. Not only are the three isomeric C3-coupling products 38 to 40 produced, but also those of 37 with the Grignard reagent, 41 and 42 (R = Et, n-Pr). All of these C–C-coupling reactions are thought to occur

C2-Alkylation of N-pyrimidylindole with vinylsilane via cobalt-catalyzed C–H bond activation

• Zhenhua Ding and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2012, 8, 1536–1542, doi:10.3762/bjoc.8.174

• sensitive to the amount of the Grignard reagent, as reduction of its loading from 100 to 60 mol % improved the yield of 3aa while suppressing the formation of byproduct 4 (Table 1, entry 10). Next, we performed screening of Grignard reagents using bathocuproine as the ligand (Table 2). Among Grignard

• the reaction, in which the reaction efficiency was strongly dependent on the alkyl group (Table 2, entries 5–10). We identified cyclohexylmagnesium bromide as the optimum Grignard reagent, which afforded 3aa in 69% isolated yield without formation of the cross-coupling product 4 between 1a and the

• Grignard reagent. With the optimized catalytic system in hand, we explored the scope of the reaction (Scheme 2). A variety of N-pyrimidylindoles participated in the reaction with vinyltrimethylsilane to afford the alkylation products 3ba–3ia in moderate yields, with tolerance of electron-withdrawing (F and

Synthesis of diverse indole libraries on polystyrene resin – Scope and limitations of an organometallic reaction on solid supports

• Kerstin Knepper,
• Sylvia Vanderheiden and
• Stefan Bräse

Beilstein J. Org. Chem. 2012, 8, 1191–1199, doi:10.3762/bjoc.8.132

• after thin-layer chromatography. A slightly higher temperature was optimal for the reaction of (3-methyl-4-nitrophenyl)carboxymethyl-polystyrene (1{i}) with the less active vinyl magnesium bromide 2{a} (Figure 3). In addition to this, we also varied the amount of Grignard reagent for the reaction of 1{h

• methoxycarboxylic acids 1{g},1{k}, which all failed in that very complex mixtures were obtained. Recently, it was reported that methoxynitroarene gave somewhat different products in the presence of Grignard reagent [48]. As reported before, ortho,ortho-unsubstituted arenes such as 1{a} were suitable substrates in

• calculated according to the nitrogen values of the elemental analysis. GP 2 - Bartoli-indole synthesis: Under an argon atmosphere, one equiv of the resin is suspended in dry THF (0.1 mmol/mL), cooled down to −40 °C and three equiv of the Grignard reagent are added, while the color of the mixture changes to

Asymmetric total synthesis of smyrindiol employing an organocatalytic aldol key step

• Dieter Enders,
• Jeanne Fronert,
• Tom Bisschops and
• Florian Boeck

Beilstein J. Org. Chem. 2012, 8, 1112–1117, doi:10.3762/bjoc.8.123

• Knochel's published modification [14] of this reaction using a lanthanum(III) chloride bis(lithium chloride) complex solution and a methyl Grignard reagent proved to be robust and produced the desired 1,3-diol 15 in high yields (87%). The 1,3-diol was found to be sensitive towards condensation to the

Novel fatty acid methyl esters from the actinomycete Micromonospora aurantiaca

• Jeroen S. Dickschat,
• Hilke Bruns and
• Ramona Riclea

Beilstein J. Org. Chem. 2011, 7, 1697–1712, doi:10.3762/bjoc.7.200

• − 57]+ ion, which is typical for anteiso-FAMEs. The synthesis of methyl 8-methyldecanoate (95) as a reference compound was started from 1-bromo-2-methylbutane (117b, Scheme 3). Copper-catalysed 1,4-addition of the respective Grignard reagent to methyl acrylate in the presence of trimethylchlorosilane

• , dimethyl sulfide, and 4-dimethylaminopyridine gave methyl 5-methylheptanoate (118b). A sequence of LiAlH4 reduction to the alcohol 119b, conversion into the bromide 120b, and Cu-mediated 1,4-addition of the Grignard reagent to methyl acrylate furnished the desired FAME 95. Its mass spectrum and retention

• -methylpentan-1-ol (119c), by similar methods as described above (Scheme 3). The alcohol 119c was transformed into the bromide 120c. The copper-catalysed Michael addition of the respective Grignard reagent to methyl acrylate yielded methyl 6-methyloctanoate (121c), which was α-methylated to 122c. Reduction with

Development of the titanium–TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

• Lukas Hintermann,
• Mauro Perseghini and
• Antonio Togni

Beilstein J. Org. Chem. 2011, 7, 1421–1435, doi:10.3762/bjoc.7.166

• started from dioxolane-diester 7 by reaction with 3-trifluoromethylphenyl or 3,5-bis(trifluormethylphenyl) Grignard reagents in the usual way to give TADDOLs T6 and T7 [92] in high yield (Scheme 5a). Interestingly, the reaction of o-trifluoromethylphenyl Grignard reagent with 7 gave hydroxyester 8 (Scheme

Functionalization of heterocyclic compounds using polyfunctional magnesium and zinc reagents

• Paul Knochel,
• Matthias A. Schade,
• Sebastian Bernhardt,
• Georg Manolikakes,
• Albrecht Metzger,
• Fabian M. Piller,
• Christoph J. Rohbogner and
• Marc Mosrin

Beilstein J. Org. Chem. 2011, 7, 1261–1277, doi:10.3762/bjoc.7.147

• density of this pyrimidine and the addition of a Grignard reagent to this heterocycle can no longer occur. Therefore, a subsequent magnesiation of 110 with TMPMgCl·LiCl (1.0 equiv) can be performed at 25 °C. After 5 min reaction time at this temperature, the resulting 6-magnesiated pyrimidine 111 is

Meta-metallation of N,N-dimethylaniline: Contrasting direct sodium-mediated zincation with indirect sodiation-dialkylzinc co-complexation

• David R. Armstrong,
• Liam Balloch,
• Eva Hevia,
• Alan R. Kennedy,
• Robert E. Mulvey,
• Charles T. O'Hara and
• Stuart D. Robertson

Beilstein J. Org. Chem. 2011, 7, 1234–1248, doi:10.3762/bjoc.7.144

• different components. The work of Knochel uncovered a special reactivity and selectivity that can be realised with a mixed lithium halide–magnesium amide complex sometimes labelled a “turbo-Grignard” reagent [8]. It has been proposed that LiCl breaks up the magnesium amide aggregates allowing more soluble

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

The preparation of 3-substituted-1,5-dibromopentanes as precursors to heteracyclohexanes

• Bryan Ringstrand,
• Martin Oltmanns,
• Jeffrey A. Batt,
• Aleksandra Jankowiak,
• Richard P. Denicola and
• Piotr Kaszynski

Beilstein J. Org. Chem. 2011, 7, 386–393, doi:10.3762/bjoc.7.49

• typically obtained from I or from II by reaction with Na2S [9][10][12][13], whereas the silacyclohexanes V and phosphorinanes VI are prepared by reacting the Grignard reagent derived from I with dichlorosilanes [14] or phosphonous dichlorides [15], respectively (Figure 1). Our research program focuses on

• % [17][38]. The downside to Method 1C is that an excess of Grignard reagent (3–4 equiv) is required; therefore, it is not economical with respect to the alkyl halide. Method 1D also uses glutaconate diester, which is reacted with an aryl iodide in the presence of Pd(0) under Heck conditions. The

• addition of a Grignard reagent to tetrahydro-4H-pyran-4-one, elimination of water, and hydrogenation of the olefin (Method 2A). Typical yields for Method 2A range from 20–30% [39][40]. The second route is the Wittig olefination of tetrahydro-4H-pyran-4-one followed by hydrogenation (Method 2B). Yields for

Photocycloaddition of aromatic and aliphatic aldehydes to isoxazoles: Cycloaddition reactivity and stability studies

• Axel G. Griesbeck,
• Marco Franke,
• Jörg Neudörfl and
• Hidehiro Kotaka

Beilstein J. Org. Chem. 2011, 7, 127–134, doi:10.3762/bjoc.7.18

• and benzaldehyde, while at −78 °C, no reaction could be observed. In contrast, the use of an excess of Grignard reagent (3 equiv) at −78 °C again led to decomposition. The application of boron trifluoride at −78 °C also led to decomposition, followed by a normal nucleophilic attack of the Grignard

• reagent on the liberated benzaldehyde. Conclusion The photocycloaddition of electronically excited carbonyl compounds to isoxazoles is clearly less effective than with other five-membered aromatic or non-aromatic heterocycles (furans, thiophenes, pyrroles, oxazoles, dihydrofurans, dihydropyrroles) [1

Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation

• Vladimir N. Boiko

Beilstein J. Org. Chem. 2010, 6, 880–921, doi:10.3762/bjoc.6.88

Recent advances in carbocupration of α-heterosubstituted alkynes

• Ahmad Basheer and
• Ilan Marek

Beilstein J. Org. Chem. 2010, 6, No. 77, doi:10.3762/bjoc.6.77

• -pyridylsilylalkyne is used, does the copper-catalyzed carbomagnesiation reaction proceed with the formation of the corresponding Grignard reagent. To prove the involvement of the pyridyl coordination, the 3- and 4-pyridylsilyl- and phenylsilyl substituted substrates were prepared and treated under similar reaction

• assumption, the carbometalated adduct was obtained in 83% yield even when using an equimolar amount of CuI with 2.0 equiv of PhMgI. Moreover, yields are drastically affected by the nature of the aryl Grignard reagent used (PhMgI, 74%; PhMgBr, 27%; PhMgCl, 0%; Ph2Mg, 0%): other Grignard derivatives were not

Synthesis and properties of calix[4]arene telluropodant ethers as Ag⁺ selective sensors and Ag⁺, Hg²⁺ extractants

• Yang Lu,
• Yuanyuan Li,
• Song He,
• Yan Lu,
• Changying Liu,
• Xianshun Zeng and
• Langxing Chen

Beilstein J. Org. Chem. 2009, 5, No. 59, doi:10.3762/bjoc.5.59

• literature procedures. 25,27-Dihydroxy-26,28-bis(phenyltelluropropoxy)-5,11,17,23-tetra-tert-butylcalix[4]arene 6 Diphenyl ditelluride (512 mg, 1.25 mmol), prepared from phenyl Grignard reagent with tellurium powder in 78% yield, was dissolved in ethanol (30 ml) and benzene (30 ml) in a 100 ml round-bottomed

Preparation and Diels–Alder/cross coupling reactions of a 2-diethanolaminoboron- substituted 1,3-diene

• Liqiong Wang,
• Cynthia S. Day,
• Marcus W. Wright and
• Mark E. Welker

Beilstein J. Org. Chem. 2009, 5, No. 45, doi:10.3762/bjoc.5.45

• greenish black. The mixture was heated to reflux for an additional 30 min after completion of the addition. The Grignard reagent thus obtained was immediately added dropwise to a solution of trimethoxyborane (4.25 mL, 38.5 mmol) in THF (25 mL) using a double-ended needle. The addition was controlled in

• have begun to prepare diethanolaminoboron substituted dienes and we communicate our first results in this area here. Results and Discussion The diethanolamine boronyl substituted diene 2 was obtained as white needles on a several gram scale from a simple procedure which involved preparing the Grignard

• reagent from chloroprene 1, adding this reagent to trimethoxyborane followed by the addition of dilute HCl and diethanolamine (Scheme 1). The boron substituted diene 2 thus obtained has C1 (δ 5.23 vs δ 5.04, 4.96 (d6-DMSO) and C3 (δ 6.31 vs. δ 6.19) hydrogen atoms which are significantly more deshielded

From discovery to production: Scale- out of continuous flow meso reactors

• Peter Styring and
• Ana I. R. Parracho

Beilstein J. Org. Chem. 2009, 5, No. 29, doi:10.3762/bjoc.5.29

• vessel 1. The reaction studied was the Kumada reaction [11][12] which involves the coupling of an aryl halide and a Grignard reagent, in this case 4-bromoanisole and phenylmagnesium chloride, to produce 4-methoxybiphenyl (4-MeOBP, R-Ar). It was also observed that anisole, 4′,4-dimethoxybyphenyl (4,4′-di

• -MeOBP, Ar-Ar) and biphenyl (BP, R-R) were obtained as reaction by-products. The catalytic cycle that we originally proposed [6] neglects the formation of the other by-products so we investigated the whole scheme in detail. The chloro rather than the bromo Grignard reagent was used, even though it was

• probe the mechanism for the reaction further. If the activation of the catalyst was important then a pre-wash with the Grignard reagent should improve the yield of the desired cross-coupled product. This was indeed found to be the case. Without any pre-wash or with a 4-bromoanisole pre-wash there was no