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

• Abstract Magnesium organometallic reagents occupy a central position in organic synthesis. The freshness of these compounds is the key for achieving a high conversion and reproducible results. Common methods for the synthesis of Grignard reagents from metallic magnesium present safety issues and exhibit a

• . Grignard reagents react with oxygen and water, yielding flammable gases and must be prepared, stored, and handled under an anhydrous inert atmosphere. Time-consuming titration is recommended but is unreliable as only the basicity is estimated. The freshness of these solutions is a key for achieving high

• conversion because the neutralization can alter the aggregation states, producing a significant batch-to-batch variability. The direct insertion of magnesium metal into organic halides is the most common method used to prepare Grignard reagents but present difficulties: (1) sluggish reactions with ordinary

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• of N-benzylidenemethylamine (40), shows the dependence of the imine yield on reaction time and temperature (Scheme 13). Higher yields of 40 were achieved at lower temperatures but longer reaction times were necessary in this case [85]. Di-tert-butyliminoxyl radicals react with Grignard reagents and

• employing organolithium reagents are presented below (Scheme 14). The Grignard reagents demonstrated very similar results that are omitted. Among the major C–O coupling product (oxime ether 42) small amounts of C–N coupling products (nitrones 43) were detected in the case of sterically unhindered

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• , and Grignard reagents. Review Copper-catalysed C–C bond-forming reactions at the heterocycle The direct synthesis of chiral heterocyclic molecules from pyridine, quinolone, or indole derivatives is advantageous due to the abundance of such building blocks. Unfortunately, establishing catalytic

• . In contrast, Grignard reagents are very favourable organometallics in terms of both their availability and atom efficiency. On the other hand, Grignard reagents are significantly more reactive than organoaluminium and organozinc reagents, rendering the catalytic control of both the regio- and

• enantioselectivity in addition reactions challenging. Nevertheless, Harutyunyan and co-workers introduced the first general catalytic methodology to access a wide variety of chiral piperidones in 2019, using Grignard reagents (Scheme 1C) [18]. Therein, a new catalytic system based on the ligand L4/Cu complex

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

• group [68] used silicon-based Grignard reagents 189 to add to conjugated heteroaromatics 188, e.g., benzoxazole (as an extension to more commonly studies ketones, esters, imines, etc.), leading to products 190–194. The heterocycle played a crucial role, as in its absence, none of the expected product

• . This same research group recently reported on the addition of silyl Grignard reagents to aziridines under copper catalysis [83]. While the use of RMgX led to high chemical yields of the desired products, the corresponding catalytic Cu/zinc reagents gave poor yields (ca. 20%; Scheme 45). A library of

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• the red phosphorus with 2-bromopyridine in potassium hydroxide/dimethyl sulfoxide emulsion, pyridylphosphine was obtained in moderate yields. Traces of phosphine oxide were present as evidenced by the observation of two phosphorus peaks in the 15P NMR spectrum. An optimized method via Grignard

• reagents has been reported by Kluver et al. [54], by which the product was isolated in excellent yield (71%). It was noted that the magnesium ions increase the water partition coefficient of these compounds since they coordinate stronger to the nitrogen atoms as compared to lithium ions. In this case

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• , and Grignard reagents to Michael acceptors. In that respect, since the pioneering example reported by Alexakis and co-workers in 1993 [5], a wide range of cyclic and acyclic electron-deficient alkenes, such as α,β-unsaturated ketones, esters, nitriles, sulfones, or nitroolefines, was intensively

• moderate to good yields, with ee values of up to 76%. When the conjugate addition was performed with Grignard reagents, significant amounts of 1,2-products and enols were formed, despite the use of cryogenic conditions. (R)-BINAP (L2) gave the best regio- and enantioselectivity, with 62% of the 1,4-product

• combination with (R)-TolBINAP (L3), a promising 85% regioselectivity was observed, without altering the enantioselectivity (90% ee), whereas only 32% of the desired 1,4- product was obtained without TMSCl [20]. With those optimized conditions, various enals and Grignard reagents were screened. Nevertheless

Friedel–Crafts approach to the one-pot synthesis of methoxy-substituted thioxanthylium salts

• Kenta Tanaka,
• Yuta Tanaka,
• Mami Kishimoto,
• Yujiro Hoshino and
• Kiyoshi Honda

Beilstein J. Org. Chem. 2019, 15, 2105–2112, doi:10.3762/bjoc.15.208

• useful properties, several research groups have developed methodologies to synthesize them. The typical synthetic methods for thioxanthylium salts include the reaction of thioxanthone with aryl bromide in the presence of n-butyllithium or Grignard reagents followed by dehydration by acids such as

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• )-6 was transformed into its higher homolog (2R,1'R)-188 employing Wittig olefination, the C=C bond reduction and Swern oxidation. The required alkyl chains were introduced by Grignard reagents and mixtures of diastereoisomeric alcohols were oxidized to ketones 189a–d. Catalytic hydrogenation allowed

Insertion of [1.1.1]propellane into aromatic disulfides

• Robin M. Bär,
• Gregor Heinrich,
• Martin Nieger,
• Olaf Fuhr and
• Stefan Bräse

Beilstein J. Org. Chem. 2019, 15, 1172–1180, doi:10.3762/bjoc.15.114

• opening of 1 with Grignard reagents enables the synthesis of aryl and some alkyl-substituted BCPs and a subsequent cross-coupling reaction [5][18]. To provide bicyclo[1.1.1]pentylamine as a building block in large-scale syntheses, Bunker et al. developed a synthesis of hydrazine BCP via a manganese

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

• (Scheme 1, reaction 3) [23][26][27][28][29][30][31][32][33]. Thus, methylenecyclopropanes have been prepared by diastereoselective addition of Grignard reagents to cyclopropenylmethyl ethers, possessing a hydroxymethyl directing substituent at C3, in the absence or in the presence of a catalyst (copper or

• iron salt) [28][29][30]. Another representative transformation is the copper-catalyzed addition of Grignard reagents to secondary unprotected cyclopropenylcarbinols which proceeds with high levels of chirality transfer to afford alkylidenecyclopropanes possessing a quaternary stereocenter at C2 [31][33

• the past few years to access hetero-substituted and/or functionalized alkylidenecyclopropanes. Review [2,3]-Sigmatropic rearrangements involving cyclopropenylcarbinol derivatives Following their report on the synthesis of chiral alkylidenecyclopropanes by copper-catalyzed addition of Grignard reagents

Regioselective addition of Grignard reagents to N-acylpyrazinium salts: synthesis of substituted 1,2-dihydropyrazines and Δ⁵-2-oxopiperazines

• Valentine R. St. Hilaire,
• William E. Hopkins,
• Yenteeo S. Miller,
• Srinivasa R. Dandepally and
• Alfred L. Williams

Beilstein J. Org. Chem. 2019, 15, 72–78, doi:10.3762/bjoc.15.8

• , North Carolina Central University, Durham, North Carolina 27707, United States 10.3762/bjoc.15.8 Abstract The regioselective addition of Grignard reagents to mono- and disubstituted N-acylpyrazinium salts affording substituted 1,2-dihydropyrazines in modest to excellent yields (45–100%) is described

• . Under acidic conditions, these 1,2-dihydropyrazines can be converted to substituted Δ5-2-oxopiperazines providing a simple and efficient approach towards their preparation. Keywords: N-acylpyrazinium salts; 1,2-dihydropyrazines; Grignard reagents; Δ5-2-oxopiperazines; regioselective addition

• -triflate pyrazinium salts to also generate γ-lactones [12]. Grignard reagents have been used as nucleophiles on a variety of N-acyl-activated pyridines in the production of natural products and biologically active small molecules [13][14][15][16][17][18][19][20]. To our surprise, there are no reports on

Non-metal-templated approaches to bis(borane) derivatives of macrocyclic dibridgehead diphosphines via alkene metathesis

• Tobias Fiedler,
• Michał Barbasiewicz,
• Michael Stollenz and
• John A. Gladysz

Beilstein J. Org. Chem. 2018, 14, 2354–2365, doi:10.3762/bjoc.14.211

• tethered by a methylene chain, in two steps in 66–68% overall yields from diethyl phosphonate ((O=)PH(OEt)2), Grignard reagents BrMg(CH2)mCH=CH2, base (NaH), and appropriate α,ω-dibromides Br(CH2)nBr [25]. Following metathesis and hydrogenation, these afford dibridgehead diphosphine oxides 15 and 16 in 14

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• activation. In 1941, Kharasch and Fields applied a cobalt salt as the catalyst for the homocoupling of Grignard reagents [28]. After 15 years, Murahashi discovered a cobalt-catalyzed chelation-assisted ortho C–H carbonylation of azobenzene and imines as the preliminary example of directing group assisted C–H

Cobalt-catalyzed nucleophilic addition of the allylic C(sp³)–H bond of simple alkenes to ketones

• Tsuyoshi Mita,
• Masashi Uchiyama,
• Kenichi Michigami and
• Yoshihiro Sato

Beilstein J. Org. Chem. 2018, 14, 2012–2017, doi:10.3762/bjoc.14.176

• that thermal cleavage of allylic C(sp3)–H bonds is possible without using highly basic organolithium or organomagnesium reagents (Grignard reagents) that react with ketones rather than deprotonating the allylic C(sp3)–H bonds. Based on the observed perfect branch selectivity, we propose the catalytic

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• benzo[7]annulenes 123–128 were prepared using 4,5-benzotropone (11) as starting material and 1H and 13C NMR studies in each series of compounds revealed strikingly different substituent effects (Scheme 21). In order to perform reactions with alkyl Grignard reagents, Bertelli’s group realized the

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• ribofuranose ring (which exists in equilibrium with the ring closed form), was exploited for C1' substitution using Grignard reagents [69]. Acid-catalyzed dehydration resulted in a diastereomeric mixture of C1'-disubstituted products 5 and 6 with an observed β/α ratio of 2:1 and 1:1, respectively. Similarily

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

• readily prepared from the corresponding aryl nitriles and organolithium or Grignard reagents, while analogous N-substituted imines are nontrivial to synthesize because of sluggish ketone/amine condensation. As such, the present reaction would complement the N-arylimine-directed alkenylation. Results and

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

• subsequently synthesized 1b, 1c, 2b, and 2c using the corresponding Grignard reagents, e.g., (4-n-PrC6H4)C6H4MgBr or 4-(trans-4-n-Pr-c-C6H10)C6H4MgBr, instead of 4-n-PrC6H4MgBr. As shown in Table 1, all reactions proceeded well to afford the corresponding adducts in acceptable to excellent yields. Tricyclic

• for multicyclic mesogens 1 and 2. Short-step approach to CF2CF2-containing carbocycles. Mechanism for the reaction of γ-keto ester 6 with vinyl Grignard reagents. First multigram-scale preparation of CF2CF2-containing multicyclic mesogens. Stereochemical assignment of the ring-closing metathesis

Acid-catalyzed ring-opening reactions of a cyclopropanated 3-aza-2-oxabicyclo[2.2.1]hept-5-ene with alcohols

• Katrina Tait,
• Alysia Horvath,
• Nicolas Blanchard and
• William Tam

Beilstein J. Org. Chem. 2017, 13, 2888–2894, doi:10.3762/bjoc.13.281

• ], organozinc or Grignard reagents [12], Rh [13], and Ru [14] catalysts. Another interesting modification of the alkene component is cyclopropanation. To date, there are a few reported examples in the literature of the cyclopropanation of 3-aza-2-oxabicyclic alkenes [15][16][17]. The addition of a cyclopropane

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• the alkene [39]. An interesting pathway of generating ylides from vinylphosphonium salts turned out to be the reaction of the latter compounds with Grignard reagents in the presence of CuBr·H2O or CuBr·Ag2CO3 (Scheme 24). The subsequent Wittig reaction allowed to obtain substituted alkenes 34 in a

• and Grignard reagents. Direct transformation of vinylphosphonium salts into ylides in the presence of potassium tert-butoxide and their subsequent Wittig reaction with aldehydes. A general method for synthesis of carbo- and heterocyclic systems by the intramolecular Wittig reaction from

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

• ester gave the corresponding aldehyde 45 which was then transformed into the α-fluoroenimine 47. This was selectively converted into the corresponding sulfinylamines using Grignard reagents to access (S)-amino acids 48, while addition of organolithium reagents gave (R)-amino acids. A sequence of N- and

• in 2011 a new synthetic route using Grignard reagents, which are widely available or can be easily synthetized in the laboratory (Scheme 14B) [46]. Unfortunately, these reagents did not react with the 4,4-difluoro-5-hydroxyallylic alcohols 73. Terminal 3,3-difluoropropenes 76 were then prepared

• starting from the commercially available protected chiral hydroxyl ester 75. Reduction to the aldehyde followed by coupling with bromodifluoropropene gave two diastereoisomers 76a and 76b separable by flash chromatography. Then, the copper-catalyzed defluorinative allylic alkylation using Grignard reagents

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

• Yaroslav D. Boyko,
• Valentin S. Dorokhov,
• Alexey Yu. Sukhorukov and
• Sema L. Ioffe

Beilstein J. Org. Chem. 2017, 13, 2214–2234, doi:10.3762/bjoc.13.220

• -nitrosoalkenes were reported so far. Among the first, Ohno and co-workers studied the addition of Grignard reagents to α-chlorooximes derived from cyclic ketones [23]. In their experiments, 2 equivalents of organomagnesium compound were used with one equivalent needed to transform α-chlorooximes into

• conjugated nitrosoalkenes from α-chlorooximes may not be compatible with further conjugate addition of Grignard reagents. Despite of these rather disappointing results, in 1977 Corey successfully employed conjugate addition of 1-lithio-1-butyne to a nitrosoalkene intermediate to introduce the butyl group at

• and angustilodine. Weinreb’s approach to the core structure of apparicine alkaloids. Weinreb’s synthesis of (+/−)-myrioneurinol via stereoselective conjugate addition of malonate to nitrosoalkene NSA9. Reactions of cyclic α-chloro oximes with Grignard reagents. Corey’s synthesis of

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

• -Paris), 45 rue des Saints Pères, 75270 Paris 06, France 10.3762/bjoc.13.153 Abstract The 5’-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2’,3’-di-O-protecting groups (R1): O-alkyl groups led to

• diastereoselective addition of a nucleophile on a carbonyl group. The latter can involve either the reduction of a ketone at C-5’ [12][33][34][35], or the addition on an aldehyde of various nucleophiles such as enolates [15][36][37][38], allylborane [39], dialkyl phosphites [40], TMSCN [41] or Grignard reagents [12

• ][17][35][42][43][44][45][46][47]. Aside from the use of chiral ligands promoting an excellent facial discrimination of the aldehyde [34], the addition of Grignard reagents usually proceed with moderate diastereoselectivity and yield (Table 1) [12][35][43][44][45][46][48]. In the course of our program

A concise and practical stereoselective synthesis of ipragliflozin L-proline

• Shuai Ma,
• Zhenren Liu,
• Jing Pan,
• Shunli Zhang and
• Weicheng Zhou

Beilstein J. Org. Chem. 2017, 13, 1064–1070, doi:10.3762/bjoc.13.105

• -selectivity [9][10]. This approach included six steps such as addition, methyl etherification, acetylation, reduction, deprotection and cocrystallization with L-proline to get 1 with a total yield of 32.89%. The subsequent improvement reported included the replacement of aryllithium by aryl Grignard reagents

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

• catalyst concentration was found. An interesting point to consider is the comparison of in-line and off-line analysis. For example, Duchateau et al. [41] described the preparation of Grignard reagents from aryl halides and magnesium using a fluidized bed reactor under continuous-flow conditions. In a