(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• ). Reaction with a Grignard reagent, hydroboration and oxidation of the organoborane were also possible in high yields (to 188). Similar to ketoprofen bioisostere 189, its inversely substituted isomer iso-189 was also accessible from 185a. Iwabuchi and co-workers also investigated the biological activity of

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• continues to be relevant. One of the methods for the synthesis of allenes was based on the interaction of bromoolefins with organolithium compounds, followed by the elimination of lithium fluoride [29][30][31]. It was logical to assume that in our case a similar reaction of the Grignard reagent 12 with

• aldehyde 9, elimination of MgBrF results in the formation of allene 11. To confirm our hypothesis, we studied the reaction of haloolefins 3 and 7 with iPrMgCl and BuLi. Thus, olefin 3a in Et2O reacted with iPrMgCl solution in THF at −80 °C to form Grignard reagent 12 and by heating the reaction mixture to

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• reagents, are commonly used in conjugate addition reactions. In the presence of Grignard reagents, the NHC-precursor salts do not require an addition of base as the Grignard reagent itself performs this role. In this way, Tomioka and co-workers [57] were able to achieve excellent regio- and

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• incorporation of a phenyl group between the glycerol and the lipid chain. The lipid chain was bonded to the aromatic ring in either ortho-, meta-, and para-position [91]. The incorporation of a phenyl moiety starts with the reaction of the Grignard reagent formed from 4-bromoanisole (10.1, the other isomers 2

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• yields (Scheme 28). In this reaction, Grignard reagent 148 was used as arylation source in excess amount as the reagent underwent homocoupling leading to the formation of biaryl systems under the reaction conditions. 1,2-Dichloro-2-methylpropane (149) was found to be an effective oxidant under the

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• from 2-bromostyrene (116) via halogen–lithium exchange and quenching with the appropriate heteroatom source (SiR2Cl2, SnMe2Cl2, GeR2Cl2, BBr3). P-Tethered dienes were synthesised via quenching of a 2-vinylphenyl Grignard reagent with phenylphosphonic dichloride (PhPOCl2). O-Tethered dienes were

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

• Benedikt Kolb,
• Daniela Silva dos Santos,
• Sanja Krause,
• Anna Zens and
• Sabine Laschat

Beilstein J. Org. Chem. 2023, 19, 176–185, doi:10.3762/bjoc.19.17

• deprotonated with LDA at −78 °C in THF and subsequently methylated to give 34 in 99%, followed by treatment with alkynyl Grignard reagent to give the tertiary alcohol 35 in 71% yield. Final elimination with MsCl and NEt3 yielded the desired enyne 25q (49%). When terpene enynes 25p and 25q were submitted to the

Total synthesis of insect sex pheromones: recent improvements based on iron-mediated cross-coupling chemistry

• Eric Gayon,
• Guillaume Lefèvre,
• Olivier Guerret,
• Adrien Tintar and
• Pablo Chourreu

Beilstein J. Org. Chem. 2023, 19, 158–166, doi:10.3762/bjoc.19.15

• -mediated cross-coupling (77% yield for the coupling step, Scheme 4a) [20]. In this cross-coupling, an α,ω-difunctionalized Grignard reagent bearing a magnesium alkoxide moiety at the end of the aliphatic chain is used as a coupling partner. Following in those footsteps, similar syntheses of other insect

• introduction of the C7–C8 linkage by a key iron-mediated cross-coupling sequence between the suitable α,ω-difunctionalized Grignard reagent and 1-bromopenta-1,3-diene as the electrophile (Scheme 6) [32]. A classic drawback of the use of dienyl halides as coupling partners is their intrinsic thermal instability

• ) European grapevine moth, c) horse-chestnut leaf miner) involving a key alkyl–alkenyl iron-mediated cross-coupling between a dienol phosphate and an α,ω-difunctionalized Grignard reagent. Cross-coupling of alkyl Grignard reagents with a) alkenyl or b) aryl halides involving EtOMgCl as additive. Total

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• synthesis started from 3-hydroxy-2-methoxybenzaldehyde (34), which was converted into Grignard reagent 35 and added onto 3-methylbut-2-enal (Scheme 6). A sequence involving Claisen rearrangement, Roskamp homologation, diazo transfer and intramolecular cyclopropanation led to intermediate 37. The hydroxy

• radical cyclization of an alkynyl ketone as the key step. The synthesis started by a Cu-catalyzed conjugate addition of the vinyl Grignard reagent, followed by TMS α-propargylation under basic conditions, affording the TMS-alkynyl ketone 76 as the major diastereomer (Scheme 11). Originally a Au-catalyzed

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C–Si bond functionalization

• Sebastien Curpanen,
• Per Reichert,
• Gabriele Lupidi,
• Giovanni Poli,
• Julie Oble and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2022, 18, 1256–1263, doi:10.3762/bjoc.18.131

• appropriate C3-silylated furfural [15] and dissolved in freshly distilled THF (0.2 M solution). The solution was cooled to 0 °C, and then the Grignard reagent (1.3 equiv in Et2O) was added dropwise (the rate of addition was equal to, or lower than 0.125 mL/min). The mixture was allowed to stir at 0 °C for 1 h

Recent developments and trends in the iron- and cobalt-catalyzed Sonogashira reactions

• Surendran Amrutha,
• Sankaran Radhika and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 262–285, doi:10.3762/bjoc.18.31

• showed better yield of the coupling products. The optimized reaction conditions consisted of 5 mol % of the utilized catalyst with the dropwise addition of Grignard reagent, and 1.2 equivalents of LiBr as an effective additive in THF that resulted in good to excellent yields of the desired products. Bolm

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• [59]. The authors proposed a plausible catalytic cycle based on a series of mechanistic studies (Scheme 3). First, FeCl2 will react with the aryl Grignard reagent to form an aryliron complex 8 which can undergo a SET with the iodoalkane to yield the radical substrate 9. A 5-exo-dig cyclization will

• produce the pyrrolidinyl methyl radical 10 which may add to the iron center to form the Fe(III) complex 11. Reductive elimination would give rise to the final product, and transmetallation with a Grignard reagent regenerates the active Fe species. Alternatively, release of the aryl radical via ipso-attack

• species is stable enough to be selectively trapped by the less sterically demanding 2° alkyl radical 29. Reductive elimination would form the difunctionalized product and transmetallation with an aryl Grignard reagent regenerates the active Fe species 26, restarting the catalytic cycle. As driving Giese

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• first prepared synthetically before its isolation from natural crude material, employing a stereoselective addition of an aryl Grignard reagent to a five-membered chiral cyclic nitrone derived from ᴅ-arabinose [2]. Its analytical data were consistent with those for the later isolated natural product

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• epoxide using vinyl Grignard reagent followed by esterification with acrylic acid (35) proved to be inefficient due to low reproducibility and poor isolation of product 36. The strategy was altered by changing the terminal epoxide 34 to an allylic alcohol (95%) utilizing dimethyl sulfonium methylide

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• F2/N2 system, but failed. Reagent 20-3 was synthesized using cesium fluoroxysulfate in 1991 (see section 1-15). Reagent 20-2 proved useful for the fluorination of both neutral and anionic nucleophiles under mild conditions. Scheme 45 illustrates some pertinent examples. Phenyl Grignard reagent

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• Wittig reaction with methylenetriphenylphosphorane (Ph3P=CH2) produced the 5′-methylene derivative [62]. Finally, oxidation with meta-chloroperbenzoic acid (mCPBA) afforded the nucleoside 97. Treatment of the nucleoside 97 with Grignard reagent PhMgBr in THF produced nucleoside 98, whose secondary

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• tetrahydroquinoline alkaloids (−)-angustureine (107) and (−)-cuspareine (108) reported by Sirvent et al. [119]. The diastereoselective addition of a Grignard reagent was a key step in this methodology. The addition proceeded with high diastereoselectivity in toluene, and the attack of the Grignard reagent occurred on

• N-methylation led to (−)-angustureine (107) in high overall yield (Scheme 31). The same methodology was applied to the synthesis of (−)-cuspareine (108), starting in this case from enantiomeric imine (RS)-104b, and using 2-(3,4-dimethoxyphenyl)ethylmagnesium bromide as Grignard reagent. A

• the Grignard reagent in this synthesis, with a 18% overall yield after seven steps from aldimine ent-126 (Scheme 35) [125]. The reaction of chiral α-siloxyl imine (SS)-126 with enolates derived from methyl ketones 131 was also investigated. The enolate was formed with LDA at −78 °C and reacted at the

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• were in situ generated from the hydroxypeptide esters 46 with a Grignard reagent (Scheme 8) [24]. To minimize the side reactions of 1-aminoalkylphosphonochloridates, a convenient method for the synthesis of phosphonodepsipeptides was described. The N-Cbz-protected 2-aminoalkylphosphinates 50 were

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• –dehydration reactions, via intermediate anti-aldol (−)-67 (Scheme 8). The addition of Grignard reagent to the enone (E)-(−)-68 occurred anti to the group TpMo(CO)2 to give adduct (E)-69, which was used in the next step without purification. The treatment of this adduct with HCl in dioxane promoted

3-Acetoxy-fatty acid isoprenyl esters from androconia of the ithomiine butterfly Ithomia salapia

• Florian Mann,
• Daiane Szczerbowski,
• Lisa de Silva,
• Melanie McClure,
• Marianne Elias and
• Stefan Schulz

Beilstein J. Org. Chem. 2020, 16, 2776–2787, doi:10.3762/bjoc.16.228

• ). A Wittig reaction with pentylphosphonium bromide resulted in bromoalkene 21 in a 9:1 Z/E-mixture. In the following step, the Grignard reagent of 21 was converted into the respective Gilman cuprate with Cu(I)I for the selective reaction with the epoxide function of (S)-22 [34]. The hydroxyester 23

Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• fresh organomagnesium reagents on a discovery scale and will do so independent from the operator’s experience in flow and/or organometallic chemistry. Keywords: Knochel–Hauser base; lithium chloride; magnesium; on-demand; packed-bed reactors; plug and flow reactor; synthesizer; turbo Grignard reagent

• (1 M) at flow rates up to 15 L/h [42]. However, in these publications, alkyl chloride substrates, which are generally more cost-effective but less reactive than the corresponding bromide or iodide, are limited. Also, the use of a LiCl solution as the reaction medium to increase the Grignard reagent

• reutilization. For optimal results, 2 equivalents of Mg* (chips/powder, 1:1) and 2 equivalents of LiCl must be used at a single time. System scope: The bicomponent column was employed to obtain the turbo Grignard reagent [45] as well as sec- and n-butylmagnesium chloride–lithium chloride complexes as THF

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• an attempt to determine the existence of radical behavior of PhMe2Si-MgMe (2), they studied the reaction of this Grignard reagent with dodecyl tosylate (1, X = OTs), which led to the formation of dodecyl silane 3 (20%) along with tridecane 4 (3%) and dodecane 5 (36%). Similarly, dodecyl bromide (1, X

• Suginome’s reagent along with LiCl, which completely overrode the need for a Grignard reagent and led to good chemical yields of the desired product (e.g., 272). In one case examined, a bulky silyl Grignard reagent gave the linear silyl derivative selectively. In addition, a quaternary carbon bearing the

Synthesis of six-membered silacycles by borane-catalyzed double sila-Friedel–Crafts reaction

• Yafang Dong,
• Masahiko Sakai,
• Kazuto Fuji,
• Kohei Sekine and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2020, 16, 409–414, doi:10.3762/bjoc.16.39

• , the transformation of the amino groups in phenoxasilin 3a into phenyl groups was carried out (Scheme 5). First, the ammonium salt 4 was prepared by treating 3a with MeOTf followed by a palladium-catalyzed cross-coupling reaction with the Grignard reagent (PhMgBr) that afforded the desired diphenylated

Formal preparation of regioregular and alternating thiophene–thiophene copolymers bearing different substituents

• Atsunori Mori,
• Keisuke Fujita,
• Chihiro Kubota,
• Toyoko Suzuki,
• Kentaro Okano,
• Takuya Matsumoto,
• Takashi Nishino and
• Masaki Horie

Beilstein J. Org. Chem. 2020, 16, 317–324, doi:10.3762/bjoc.16.31

• to afford the regioregular polythiophene in which 2,5-dihalo-3-substituted thiophene 1 is employed as a monomer precursor, converting to the corresponding organometallic monomer by a halogen−magnesium exchange reaction with a Grignard reagent. The employment of 1 leading to polythiophene has been