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

Cs₂CO₃-Promoted reaction of tertiary bromopropargylic alcohols and phenols in DMF: a novel approach to α-phenoxyketones

• Ol'ga G. Volostnykh,
• Olesya A. Shemyakina,
• Anton V. Stepanov and
• Igor' A. Ushakov

Beilstein J. Org. Chem. 2022, 18, 420–428, doi:10.3762/bjoc.18.44

• -phenoxyketones, the most common methodologies are base-catalyzed alkylation of the corresponding phenols with halo- [28][29][30] and mesyl [31][32][33] ketones (Scheme 9), the preparation of which are not always selective and high-yielded. The ring opening of ArOCH2-epoxides [34][35], the SmI2-catalyzed

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• maintaining animals’ physiology, by acting on blood clotting and regulating bone calcification [10]. In animals, menadione can be converted in vitamin K2 in the intestinal tract, by intestinal microbiota [10]. In humans, the menadione–vitamin K2 conversion occurs after its alkylation in the liver [11

• useful alkylation approach is the Kochi–Anderson method [76] (or also known as Jacobsen–Torssell method [77][78]), via oxidative decarboxylation, where the quinone reacts with a carboxylic acid in the presence of silver(I) nitrate and ammonium or potassium peroxydisulfate. Nucleophilic free radicals are

• -workers synthetized 10 using a much simpler way (Scheme 1) [80]. These authors reported the methylation and alkylation of 1,4-naphthoquinone (1) in the presence of (NH4)2S2O8 and AgNO3 as catalyst to obtain 10 in 60% yield. Recently, Onuki and co-workers conducted dimerization reactions of 10, exploring

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• [Pd(C3H5)Cl]2 and ligand L1 (Scheme 2) [11]. The reaction, that could also be considered as Friedel–Crafts type, intramolecular allylic alkylation, delivered nine-membered ring bearing 3,4-fused indoles 2 in moderate to good yields. In the asymmetric version of the reaction catalyzed by [Ir(cod)Cl]2

• synthesis of pyrano[2,3-e]indol-3-ols 41 via trifluoroethanol-mediated intramolecular ring-opening cyclization of 4-(2-oxiranylmethoxy)indoles 40 which were prepared by O-alkylation of 4-hydroxyindole 38 using epoxy tosylates 39 as the alkylating agents, followed by (in selected cases) N-tert

• -butyloxycarbonylation and N-alkylation (Scheme 14) [25]. The C5 cyclization regioselectivity and trans-diastereoselectivity were not influenced by the electronic nature of the indole-N-substituent. Conclusion As illustrated by these studies, SEAr-based intramolecular cyclization and annulation reactions of 3,5

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• catalysis relies on the deprotonation of one of the substrates, but basic conditions may limit the applicability of this methodology. A unique base-free variant of chiral phase-transfer catalytic alkylation of 2-oxindoles was developed by Connon and co-workers [23]. Pentacarboxycyclopentadienes are a unique

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• transformations. Organometallics are the most commonly used catalysts to promote C–C bond formation. In addition, other so-called classical reactions are also widely used, such as Friedel–Crafts alkylation and acylation, Wittig and Horner–Emmons reactions, carbonyl addition/substitution, α-alkylation, aldol

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

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

• Nicolai Wippert,
• Martin Nieger,
• Claudine Herlan,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2021, 17, 2773–2780, doi:10.3762/bjoc.17.187

•  1, the alkylation protocol did not give a selective conversion in favor of one of the generated isomers. The protocol was not changed or adapted to gain a higher selectivity of one of the isomers, as both regioisomers were used in the subsequent syntheses. For the derivatives 12h and 13c, we were

• able to exemplarily determine the molecular structure by X-ray crystallography, proving the regioisomer obtained in the alkylation reaction (Figure 2). While isomer 12 was used for the synthesis of pyrazolo[3,4-d][1,2,3]-3H-triazine derivatives of general structure 5, the isomer 13 was intended to

• -triazine derivatives. Molecular structures of compounds 12h (A) and 13c (B) representing both possible regioisomers of the alkylation reaction (displacement parameters are drawn at the 50% probability level). The X-ray data corroborate the obtained NMR data. Graphical overview about selected pyrazolo[1,2,3

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• values of up to 95% and very good yields (≈99%) in all cases (Table 11) [45]. Guo et al. synthesized a variety of benzoindolizidines (56) from α,β-unsaturated aminoketones 54 through intramolecular domino aza-Michael addition/alkylation reactions. The reactions were carried out in the presence of

• and thioureas were screened for the enantioselective N-alkylation of isoxazolin-5-ones via a 1,6-aza-Michael addition of isoxazolin-5-ones 64 to p-quinone methides (p-QMs) 65 to give isoxazolin-5-ones 67 bearing a chiral diarylmethyl moiety attached to the N atom. The best result in terms of

• aza-Michael/alkylation reaction catalyzed by cinchona alkaloid-derived quaternary ammonium salts. Asymmetric aza-Michael synthesis of isoindolinones. Asymmetric aza-Michael addition reaction catalysed by chiral bifunctional thiourea. Enantioselective 1,6-aza-Michael addition of isoxazolin-5-ones to p

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• alkylation of the anion of pyrrolidin-2-one (16) with ethyl bromoacetate to afford the known compound ethyl 2-(2-oxopyrrolidin-1-yl)acetate (17) [31][32][33] in 77% yield. Thionation of 17 with Lawesson’s reagent in toluene at 80 °C gave the thione 18 as a yellow oil (86%). Reaction of 18 with phenacyl

• 19a. This enaminone-based method for constructing a pyrrole ring is similar to that in our reported routes to lamellarin alkaloids, in which N-alkylation of (Z)-configured 3,4-dihydroisoquinoline-derived enaminones with ethyl bromoacetate under either conventional [49][50] or microwave [51] heating

• such enaminones by the route shown in Scheme 4. Alkylation of piperidin-2-one (23) with ethyl bromoacetate followed by treatment of the resulting lactam [66][67] with Lawesson’s reagent in toluene at 80 °C gave the thione 24 in 83% overall yield. Reaction of 24 with phenacyl bromide and its 4-methoxy

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• alkylation Under mild conditions, copper salts are able to catalyze olefinic C–H functionalization or allylic alkylation, thus allow introducing alkenyl or allyl groups into organic molecules. Alkenylation and allylation reactions have been extensively investigated under thermal conditions. However, only few

• transferred electrons to organic halides, thereby achieving the cross-coupling. The detailed mechanistic studies are shown in section 3.2. In 2013, Fu and co-workers [81] reported the photoinduced copper-catalyzed alkylation of carbazoles 41 with alkyl halides 42 and completed the corresponding mechanistic

• functionalization of stable alkanes C(sp3)–H is generally difficult. In 2020, the König group [97] explored the photoinduced copperII catalyzed N–H alkylation of a broad range of nitrogen-containing compounds 61 with unactivated alkanes 62. A tert-butoxy radical abstracted a hydrogen atom from the alkane via the

Direct C(sp³)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

• Siyu Wang,
• Lianyou Zheng,
• Shutao Wang,
• Shulin Ning,
• Zhuoqi Zhang and
• Jinbao Xiang

Beilstein J. Org. Chem. 2021, 17, 2505–2510, doi:10.3762/bjoc.17.167

• (sp3)–H allylic alkylation of 2-alkylpyridines with Morita–Baylis–Hillman (MBH) carbonates is described. A plausible mechanism of the reaction might involve a tandem SN2’ type nucleophilic substitution followed by an aza-Cope rearrangement. Various alkyl substituents on 2-alkylpyridines were tolerated

• in the reaction to give the allylation products in 26–91% yields. The developed method provides a straightforward and operational simple strategy for the allylic functionalization of 2-alkypyridine derivatives. Keywords: 2-alkylpyridines; allylic alkylation; aza-Cope rearrangement; catalyst-free

• synergistic catalyzed allylic alkylation between electron-deficient 2-ethyl benzoxazoles and MBH carbonates by the combination of a Lewis base and a metal salt [24]. In their studies, although pyridine derivatives were also applicable in the reaction, the presence of a strong electron-withdrawing NO2 group

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• (Scheme 1a) [17][18][19][20][21][22]. Early in 2015, the Ackermann group reported the first example of a low-valent Co-catalyzed C–H alkenylation of 2-pyridinylferrocene [23]. In 2017, the Butenschön group reported the ortho-C–H alkylation and arylation of ferrocene derivatives enabled by a combination of

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• structural motifs to provide the functionalized pyridine and pyrrole derivatives. The functionalization reactions cover iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, alkylation, selenylation, sulfenylation, amidation, esterification, and hydroxylation. We also briefly

• functionalizations of pyrrole derivatives, such as iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, and alkylation. The proposed mechanism generally involves two kinds of intramolecular cyclizations: one is 6-endo-dig cyclization to promote the formation of pyridine ring

Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels–Alder reaction

• Ren-Jie Fang,
• Chen Yan,
• Jing Sun,
• Ying Han and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2021, 17, 2425–2432, doi:10.3762/bjoc.17.159

• scope of this domino Diels–Alder reaction, another kind of 3-vinylindoles was employed in the one-pot reaction. First, the 3-(indol-3-yl)-1,3-diphenylpropan-1-ones prepared through Friedel–Crafts alkylation of indole with chalcones, were oxidized by DDQ in acetonitrile to generate in situ the expected

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• (preQ1) [1]. Thus far, present-day riboswitches have only been known to bind – but not to be able to react – with their ligands [2][3]. This new finding now opens exciting avenues for the development of RNA labeling tools [4], in particular, for RNA methylation, and more generally, for RNA alkylation. To

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• synthesis of a potent CRTH2 receptor antagonist. Keywords: alkylation; base-free; cinchona alkaloids; CRTH2 antagonist; hydrogen-bonding; oxindole; phase-transfer catalysis; Introduction The 2-oxindole scaffold is an important motif present in a myriad of natural products. Among 2-oxidole derivatives, 3,3

• highly valuable synthetic building blocks [5][6][7][8][9][10][11][12]. Both pyrroloindolines 1 and spirooxindoles 2 are conceivably available from key 3,3-disubstituted intermediates 3, which could be prepared via an enantioselective SN2 alkylation involving enolate 3a (Figure 1B). The versatility of

• charged intermediates, could be an excellent methodology for the enantioselective SN2 alkylation of enolates derived from the 2-oxindole core [13][14][15][16][17][18][19][20][21][22][23]. In recent years, several examples regarding the alkylation of 3-subsituted-2-oxindoles, via asymmetric phase-transfer

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• heterolytic cleavage of HCl as displayed in Scheme 7 [55]. Moreover, other catalysts with amine functional groups were found more efficient in the enantioselective α-alkylation of aldehydes (Scheme 10b) [48] or in the asymmetric Mannich synthesis of α-amino esters using Takemoto’s bifunctional catalyst 44 [67

• catalyzed by chiral squaramide 37 by Jacobsen et al. Bis-urea-catalyzed enantioselective fluorination of a) β-bromosulfides and b) β-haloamines by Gouverneur et al. a) Bifunctional thiourea anion-binding – basic/nucleophilic catalysts. Selected applications in b) enantioselective α-alkylation of aldehydes

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• products 39 with good regioselectivities. The authors proposed a tentative visible-light-driven radical chain mechanistic profile with nickel chain-walking as a key step to rationalize the C–H arylation process [78]. Alkylation The direct functionalization of C–H bonds in alkyl groups is a fundamental but

• nickel catalysis is also often employed to C(sp3)‒H alkylation transformations. For example, in 2017, MacMillan and co-workers reported a selective C(sp3)–H alkylation protocol via polarity-matched hydrogen atom transfer (HAT) using photoredox and nickel catalysis [85]. This method works through

• -catalyzed C–H alkylation strategy to use the readily available inexpensive organo-photocatalyst benzaldehyde as the HAT photocatalyst under UVA irradiation [68][86]. Thus, the combination of NiBr2·glyme/dtbbpy, benzaldehyde as both the photosensitizer and hydrogen abstractor, and K2HPO4 as a base under

Transition-metal-free intramolecular Friedel–Crafts reaction by alkene activation: A method for the synthesis of some novel xanthene derivatives

• Tülay Yıldız,
• İrem Baştaş and
• Hatice Başpınar Küçük

Beilstein J. Org. Chem. 2021, 17, 2203–2208, doi:10.3762/bjoc.17.142

• significance were synthesized by developing a new synthesis method. In order to obtain xanthene derivatives, the original alkene compounds to be used as the starting materials were synthesized in four steps using appropriate reactions. A cyclization reaction by intramolecular Friedel–Crafts alkylation was

• hours. As a result, an alkene compound was used for activation with TFA in the synthesis of xanthene through intramolecular Friedel–Crafts alkylation for the first time. Keywords: alkene activation; intramolecular Friedel–Crafts alkylation; trifluoroacetic acid; xanthene; Introduction The interest in

• ]. Therefore, there has been an increase in arylation methods using Friedel–Crafts alkylation (FCA) protocols without transition metals [35][36]. Environmentally friendly methods, in which metal-free catalysts are used, have come to the fore and are gaining importance because there are many disadvantages of