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

• , whereas when the reaction was performed in THF alone (at 20 °C), the yield improved significantly (92%, Scheme 3). The efficient iron-mediated alkylation of dienyl phosphates, proceeding with an excellent retention of stereochemistry, was then successfully used in the introduction of the alkyl–alkenyl

• pheromone 4 can be obtained in a convergent total synthesis with a key iron-mediated cross coupling starting from sorbic acid and a commercially available α,ω-chloroalcohol in 4 steps, with an overall 38% yield. This method can also be used for the alkylation of dienyl bromides by classic aliphatic or

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• reverse (3 + 2) cycloaddition which expels a heteroatomic anion via a β-elimination-type mechanism somewhat similar to a classical Grob-type fragmentation. Similarly, 1,3-dithiolanes undergo fragmentation at relatively low reaction temperatures, limiting their synthetic application to alkylation with

• dienophiles 7 and 27. 4 Alkylation chemistry of 1,4-dithianes and 1,4-dithiins: stereocontrolled synthesis of Z-alkenes As mentioned in chapter 2 of this review, Palumbo and co-workers found that 5,6-dihydro-1,4-dithiins are relatively resistant to β-elimination in their lithiated form (Scheme 6e), and this

• opens up options for Corey–Seebach-type alkylation reactivity with a wider range of electrophiles. The method is demonstrated by the smooth lithiation and subsequent alkylation of the acetophenone-derived dithiin 50 (Scheme 10a) [42]. Palumbo’s elegant overall approach to dihydrodithiin-mediated

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• starting from the commercially available triethyl phosphonoacetate (14, Scheme 2a). The deprotonation of 14 with NaH followed by alkylation using (iodomethyl)trimethylsilane afforded phosphonate 15 in 60% yield (7.0 g). Its subsequent Horner–Wadsworth–Emmons reaction with isovaleraldehyde resulted in the

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• limited substrate scopes (Scheme 1a). With the rapid development of sustainable chemistry, developing low-cost and transition-metal-free photocatalytic methods has become a strategic priority. In 2019 [54], the groups of Fu and Shang pioneered the photocatalytic decarboxylative alkylation of silyl enol

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

• Julian Spils,
• Thomas Wirth and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

• Friedel–Crafts alkylation followed by an anodic oxidative cyclization yielded a defined set of cyclic iodonium salts in a highly substrate-dependent yield. Keywords: electrochemistry; flow chemistry; hypervalent compounds; iodine; oxidation; Introduction Hypervalent iodine compounds (HVI) are well

• . Conclusion In summary, we have developed the first multi-step continuous-flow procedure for the generation of cyclic six-membered diaryliodonium salts. Starting from easily accessible benzyl acetates we were able to combine a Friedel–Crafts alkylation with a subsequent anodic oxidative cyclization in flow

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• -fused tetracycle instead, were reported to possess NF-kB-inhibitory activity and anticancer activity against NCI H-929 cancer cell lines (Scheme 6) [39]. In 2021 Lu’s group reported the total synthesis of members of both meroterpenoid families based on a highly chemoselective α-alkylation in the

• thermodynamic position of a Wieland−Miescher ketone derivative 68 with benzyl bromide 69. Despite the challenging O- and C7-alkylations that required suppression, the desired C9-alkylation was achieved in 72% yield under thermodynamically controlled conditions (t-BuOK in THF at −40 °C). This coupled the terpene

• 167 at 390 nm in the presence of NaHCO3 in CH3CN/t-BuOH, 5:1 to provide 168 in 55% yield (Scheme 14) [91]. Alkylation of the tetracycle, followed by epimerization of the C2 center and radical deoxygenation, or alternatively SN2 etherification, provided the common scaffold 170. The latter can serve as

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• concerned the separation of an O-alkylation product where a PTC was needed as part of the process prior to the next synthetic step [56]. Interestingly, for small scale examples anisole worked well as a solvent for both telescoped reactions. However, in a long run a gravity separator was favored because of

• membrane fouling after 1 hour. An automated fill-empty gravity separator was also used for the separation of phases in a scale up of an N-alkylation reaction reported by Eli-Lilly as an alternative to the Zaiput membranes that were better used for rapid screening of conditions [57]. The use of these

• -alkylation reaction which includes quenching, phase separation, and final filtration. After a thorough study of conditions to avoid clogging, a long run processing >100 g was achieved, giving the product in 95% yield and >99% purity [116]. The same authors also reported the crystallization of a simple

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, the authors followed the strategy developed previously by Marinovi’s group to form the bicyclo[3.2.1]octane moiety [39]. The synthesis started from 64 with a one-pot Birch reduction/alkylation with vinyl bromide 65, affording 66 in 68% yield over two steps. Next the construction of the bicylo

Functionalization of imidazole N-oxide: a recent discovery in organic transformations

• Koustav Singha,
• Imran Habib and
• Mossaraf Hossain

Beilstein J. Org. Chem. 2022, 18, 1575–1588, doi:10.3762/bjoc.18.168

• reactions with elemental sulfur [23][24][25], resulting in the generation of non-enolizable imidazole-2-thiones. At first, the alkylation of 2-unsubstituted imidazole N-oxides 40 took place in the presence of an equimolar quantity of benzyl bromide in CH2Cl2 at rt providing the (N-benzyloxy)imidazolium

1,4,6,10-Tetraazaadamantanes (TAADs) with N-amino groups: synthesis and formation of boron chelates and host–guest complexes

• Artem N. Semakin,
• Ivan S. Golovanov,
• Yulia V. Nelyubina and
• Alexey Yu. Sukhorukov

Beilstein J. Org. Chem. 2022, 18, 1424–1434, doi:10.3762/bjoc.18.148

• triple alkylation of ammonia with α-halohydrazones 9a–e following a protocol previously developed by us [35] (Scheme 2a). Halohydrazones 9a–e were prepared by condensation of readily available chloroacetone or bromoacetaldehyde (generated from the corresponding diethyl acetal) with hydrazides or

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

• Sanaz Ahmadipour,
• Alice J. C. Wahart,
• Jonathan P. Dolan,
• Laura Beswick,
• Chris S. Hawes,
• Robert A. Field and
• Gavin J. Miller

Beilstein J. Org. Chem. 2022, 18, 1379–1384, doi:10.3762/bjoc.18.142

• active site thiohemiaminal (amine to imine oxidation) or disulfide formation, respectively. Additionally, C6–Cl derivative 9 could probe cysteine alkylation. Reported herein is our exploration of this synthesis and the evaluation of GDP 6-chloro-6-deoxy-ᴅ-mannose 18 against GMD. Results and Discussion

• the GMD-19 incubation time to overnight, followed by protein-MS analysis, but found no evidence of sugar nucleotide–protein conjugation; by contrast a positive control treating GMD with iodoacetamide showed multiple alkylation of the protein (see Figure S4 in Supporting Information Information File 1

• accepted. Evaluation of GDP 6-chloro-6-deoxy-ᴅ-mannose suggests that the ligand can bind to GMD, but that targeting inhibitive S-alkylation of an sp3-hybridised C6 electrophilic probe is ineffective here. a) Proposed oxidative pathway for provision of GDP-ManA 5 from GDP-Man 1, C6 stereochemistry of 3 is

Ionic multiresonant thermally activated delayed fluorescence emitters for light emitting electrochemical cells

• Merve Karaman,
• Abhishek Kumar Gupta,
• Subeesh Madayanad Suresh,
• Tomas Matulaitis,
• Lorenzo Mardegan,
• Daniel Tordera,
• Henk J. Bolink,
• Sen Wu,
• Stuart Warriner,
• Ifor D. Samuel and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2022, 18, 1311–1321, doi:10.3762/bjoc.18.136

• -dibromobutane in moderate yield, followed by a second alkylation step with 1-methylimidazole in very good yield. DiKTa-OBuIm was isolated as its hexafluorophosphate salt following anion metathesis with NH4PF6. DiKTa-DPA-OBuIm was obtained also in three steps at 35% overall yield from compound 4 using a similar

Ferrocenoyl-adenines: substituent effects on regioselective acylation

• Mateja Toma,
• Gabrijel Zubčić,
• Jasmina Lapić,
• Senka Djaković,
• Davor Šakić and
• Valerije Vrček

Beilstein J. Org. Chem. 2022, 18, 1270–1277, doi:10.3762/bjoc.18.133

• both isomers is, therefore, a competitive process. This confirms that the adenine anion behaves as an ambident nucleophile with two competing reaction centers at the N7- and N9-position [26]. It is known that acylation [25] or alkylation [27][28][29] of adenine is rarely regiospecific, and mixtures of

• N7- and N9-isomers are usually obtained. In some cases, the acylation of adenine may also occur at the exo-amino group (N6) [30][31]. In general, the literature on the regioselectivity of alkylation of adenines/purines is more abundant, includes an array of reaction conditions (base, solvent

• in the alkylation of purines were reported earlier [40]. Now, we demonstrate for the first time that similar effect is operative in the acylation of purines. It is evident from the results in Table 1 that the N9/N7 ratio increases with the increasing size of the substituent at the exocyclic amino

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

• details). We also contemplated the use of alkyl iodides as electrophiles. Methylation with methyl iodide was efficient, as shown through the preparation of 28 in 61% yield from 4c. In contrast, higher alkyl iodides, such as ethyl iodide, failed to provide the alkylation product (i.e., 29) and only

A versatile way for the synthesis of monomethylamines by reduction of N-substituted carbonylimidazoles with the NaBH₄/I₂ system

• Lin Chen,
• Xuan Zhou,
• Zhiyong Chen,
• Changxu Wang,
• Shunjie Wang and
• Hanbing Teng

Beilstein J. Org. Chem. 2022, 18, 1032–1039, doi:10.3762/bjoc.18.104

• the methylation reagents and the reductive amination reactions by using formaldehyde or paraformaldehyde as the “indirect” alkylation reagents [16][17][18][19]. Recently, a variety of promising methylating agents or C1 sources such as formic acid [20][21], methanol [22][23][24][25][26][27][28][29][30

• ][31] and carbon dioxide (CO2) [32][33][34][35][36][37][38][39] have been developed for the N-methylation of amines. However, these N-alkylation methods often require the employment of expensive catalysts, and the N-alkylation of primary amines generally does not stop with monomethylation as expected

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• -phenylphosphinamide (92a) and chloromethyl N,N’-dimethyl-N,N’-diphenylphosphondiamide (92b) via an intramolecular Friedel–Crafts alkylation. Although they tried several different amide derivatives, only phosphinamide 92a and phosphonic diamide 92b gave the corresponding 1-methyl-1,3-dihydrobenzo[d][1,2]azaphosphole 2

• intramolecular nucleophilic dearomatization and protonation or electrophilic alkylation reactions, affording the corresponding dihydronaphthylene-fused γ-phosphinolactams 135–142. Methanol was used as the electrophile for protonation, while methyl iodide and allyl bromide were used as electrophiles for

• alkylation. A remarkable difference compared with the diphenylphosphinamides is the fact that the current reactions proceeded with excellent regio- and stereoselectivities and yields in THF without the use of the carcinogenic cosolvent HMPA (Scheme 24) [51]. With benzaldehyde as an electrophile, both

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

• Virginija Jakubkiene,
• Gabrielius Ernis Valiulis,
• Markus Schweipert,
• Asta Zubriene,
• Daumantas Matulis,
• Franz-Josef Meyer-Almes and
• Sigitas Tumkevicius

Beilstein J. Org. Chem. 2022, 18, 837–844, doi:10.3762/bjoc.18.84

• to differently substituted pyrimidine rings via a methylene group bridge of varying length as potential HDAC inhibitors is described. The target compounds were obtained by alkylation of 2-(alkylthio)pyrimidin-4(3H)-ones with ethyl 2-bromoethanoate, ethyl 4-bromobutanoate, or methyl 6-bromohexanoate

• both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively. Keywords: alkylation; aminolysis; HDAC inhibitors; hydroxamic acid; pyrimidine; Introduction Histone deacetylases (HDACs) are a family of intracellular proteins responsible for removing acetyl groups in histones

• ][28][29][30]. In this work, the pyrimidine-based hydroxamic acids were synthesized by aminolysis of the corresponding esters. The required esters 3 and 4 were obtained by alkylation of pyrimidinones 1 and 2 with ethyl 2-bromoethanoate in triethylamine in the presence of tetrabutylammonium bromide at

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• . On the other hand, the tetrahydrospiro[carbazole-3,5'-pyrimidine] 4 can be converted to aromatized spiro[carbazole-3,5'-pyrimidine] 3 through the oxidation of DDQ. In the absence of the effective dienophile, the normal Friedel–Crafts alkylation of 2-methylindole with aromatic aldehyde gives the well

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• , the expansion of our previously reported propiophenone family of reagents was envisioned as suitable alternative to produce a bench stable, organic soluble, and iodine-free perfluroalkylation source. In 2017, our group developed a metal-free and redox-neutral protocol for the photoinduced alkylation

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• and warm odor; interestingly, it is also strongly antiseptic [9]. In 2005, Poliakoff and co-workers developed a synthesis of thymol by alkylation of m-cresol (39) in supercritical carbon dioxide (scCO2) using γ-Al2O3 in a packed-bed reactor (Scheme 9) [40]. In the presence of Brønsted-acidic Nafion

• SAC-13, alkylation of m-cresol with isopropanol proceeds via a Friedel–Crafts-type mechanism in much lower selectivity. In contrast, the authors proposed that employing γ-Al2O3 as Lewis acid catalyst, reaction of 39 and isopropanol leads to isopropyl ether 40. This intermediate undergoes a Fries-type

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• 180 °C at 4.5 MPa for 7.5 min. These conditions allowed to suppress the decomposition of the N-alkylation product 78 by using a 1/8“-reactor. The subsequent purification was realized by a clever catch and release protocol based on a silica column, yielding iloperidone (80, 67%). The tricyclic

• included a carboxylation and a Parham cyclization and hence a Grignard alkylation of ketone 82 using reagent 81. The resulting alcohol 83 was subjected to thermolysis that led to water elimination. This step proceeded in just 30 s by employing the inductive heating technique. The crude elimination product

• fixed-bed materials serving as catalysts: A. with copper metal, B. with Au-doped MagSilicaTM, and C. with Pd-doped MagSilicaTM. Two step flow protocol for the preparation of 1,1'-diarylalkanes 77 from ketones and aldehydes 74, respectively, and boronic acids 76. O-Alkylation, the last step in the

Synthesis of sulfur karrikin bioisosteres as potential neuroprotectives

• Martin Pošta,
• Václav Zima,
• Lenka Poštová Slavětínská,
• Marika Matoušová and
• Petr Beier

Beilstein J. Org. Chem. 2022, 18, 549–554, doi:10.3762/bjoc.18.57

• compounds 8, 20 and 21 albeit in low yields. Due to the extremely low isolated yield of compounds 20 and 21, we looked for an alternative more efficient procedure. In 2008 Sun et al. [32] described a method of karrikin alkylation in position 7 via direct metalation with lithium bis(trimethylsilyl)amide

• (LiHMDS), followed by the addition of an alkyl halide. Application of this method to 8 provided the target molecule 21 in good yield (Scheme 4). It has to be mentioned that the metalation proceeds exclusively at C7, and thus cannot be used for the preparation of 20 via alkylation at C5. Our attempt to

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• were coupled with a benzoic acid-based stopper using N,N′-diisopropylcarbodiimide (DIC) and tributylphosphine (26–75% yield). The isolated rotaxanes were then used for subsequent reductive N-alkylation to obtain the tert-amine-type rotaxanes (R)-29a–f in yields of 67–92%. Finally, dimethyldioxirane

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban

• Martin Vrbický,
• Karel Macek,
• Jaroslav Pochobradský,
• Jan Svoboda,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2022, 18, 438–445, doi:10.3762/bjoc.18.46

• utilized, which consisted of alkylation of aniline 3 by methyl bromoacetate, followed by introduction of the Boc group into intermediate Int-17a, and final reduction of Int-17b with DIBAL-H (Scheme 1). For the study of the asymmetric Henry reaction aldehydes 15–20, nitromethane, and highly enantioselective

Tetraphenylethylene-embedded pillar[5]arene-based orthogonal self-assembly for efficient photocatalysis in water

• Zhihang Bai,
• Krishnasamy Velmurugan,
• Xueqi Tian,
• Minzan Zuo,
• Kaiya Wang and
• Xiao-Yu Hu

Beilstein J. Org. Chem. 2022, 18, 429–437, doi:10.3762/bjoc.18.45

• supramolecular assembly with a two-step FRET process by the utilization of a metallacycle-tetraphenylethylene (TPE) donor and eosin Y (EsY) and sulforhodamine (SR101) as first and second acceptors, respectively. The resulting supramolecular energy transfer system was applied to the alkylation of C–H bonds via a