α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• chiral induction. It should be mentioned here that our attempts to trap the intermediate enolate with a carbon electrophile other than carbonyl acceptors (i.e., iodomethane) were not successful and protodemetalation of the enolate outcompeted methylation. Conclusion In conclusion, we have demonstrated

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

• building unit. The synthesis of this intermediate was prepared as a racemic (Figure 24) or stereocontrolled form. One strategy to prepare rac-AMG starts from 24.1 (24.1 can be prepared from glycerol) [120][121]. Methylation of 24.1 is readily achieved by the deprotonation of the secondary alcohol with NaH

• followed by the methylation with iodomethane. Then, the cleavage of the acetal occurs by reaction with BH3·THF to give 24.3. Then, the primary alcohol was alkylated with the lipid chain (e.g., C16H33) to produce 24.4. Finally, the benzyl protecting group was removed by catalytic hydrogenolysis to produce

• mono-unsaturated lipid chain [142]. This synthesis starts from ᴅ-mannitol that was protected with 4-methoxybenzaldehyde to produce 32.1 (Figure 32) [143]. Then, the methylation of the two alcohol functions produced 32.2. A regioselective reductive cleavage of the acetal was achieved by using either

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• -catalyzed radical decarboxylative cyclization. Synthesis of compound 5. Photoredox-catalyzed radical decarboxylative cyclization of 5. Synthesis of tryptophan derivatives 8 and 10. Methylation of 11 and the formal total synthesis of (±)-6,7-secoagroclavine. Photoredox-catalyzed radical decarboxylative

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• amides was quite wide, including different EWGs and EDGs, as well as heterocycles, ortho-substitution was not tolerated. The authors applied the methodology for the synthesis of biologically important benzo[c]phenanthridine derivatives 117. Through methylation and subsequent aromatization of the

Synthesis and reactivity of azole-based iodazinium salts

• Thomas J. Kuczmera,
• Annalena Dietz,
• Andreas Boelke and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 317–324, doi:10.3762/bjoc.19.27

• to iodide and bromide were performed giving the salts 10a and 10b in excellent yields [27]. A copper-catalyzed iodination gave the diiodinated product 11 in quantitative yield [42]. Finally, N-methylation of 5aa was performed, to yield the dicationic salt 5av in 56% yield without decomposition of the

• center intact. Treatment of the ortho-pyrazole-substituted salt 5bb with MeOTf resulted in a selective benzimidazole N-methylation. A reaction on the pyrazole nitrogen is impeded due to its coordination with the iodane’s σ-hole (Scheme 2a). Besides nitrogen-substitution, the benzimidazole C-2 position of

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

• asymmetric conjugate reaction of commercially available 81 and 82 using Fletcher’s protocol (94% ee) [44]. A subsequent intramolecular arylation in the α-position of the ketone of 83, catalyzed by a Pd(II)–NHC [45], followed by methylation, provided cis-decalin 84 (Scheme 7). Appropriate redox modifications

Synthetic study toward tridachiapyrone B

• Morgan Cormier,
• Florian Hernvann and
• Michaël De Paolis

Beilstein J. Org. Chem. 2022, 18, 1741–1748, doi:10.3762/bjoc.18.183

• carbanions of 1,3-dithiane [27], allyl [27], and methyldienylbenzene groups [31] to compound 2 were demonstrated, this result amounts to the first grafting of an aromatic nucleophile to the motif. The construction of the vicinal quaternary carbon of 6b was next investigated by methylation of the highly

• to 2 in the presence of n-BuLi, the direct transfer of the crotyl appendage failed, likely compromised by the steric hindrance of the nucleophile [31]. To alleviate this shortcoming, the crotyl appendage of 8 was assembled by methylation of the allylic pyrone counterpart (Scheme 5). Implemented by

• exposing 2 to the combination of reagents tri(n-butyl)allylstannane/n-BuLi (2 equiv) followed by the treatment with MeI, the crotyl derivative 8 was directly isolated in 55–60% yield (5 g scale) via the regioselective methylation of the intermediate vinylogous enolate 10·Li. The preparation of aldehyde 9

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

• had previously reported a similar rearrangement for the synthesis of a grayanane-type skeleton [21]. Further methylation and protecting group interconversions lead to an advanced tricyclic structure 5, which could be further elaborated into relay intermediate 1. Although Matsumoto’s approach does not

• ketone methylation gave access to 56. Directed C1–C5 vanadium-mediated epoxidation followed by DBU treatment and TBS deprotection afforded 57 in one pot. The tertiary alcohol 58 was obtained as a single diastereomer after hydration of position C18. Subsequent reduction with DIBAL-H gave the desired

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• functional transformation from 10, which itself would be prepared through methylation and conjugate addition from Pauson–Khand adduct 11. This cyclopentenone could be readily accessed from 1,7-enyne 12 which could be obtained through the reported procedure [35] from the commercially available 5-hexenoic acid

• constructing the D ring is currently undergoing. Conclusion In summary, we have developed an approach to assemble the tricyclic skeleton of aberrarone through stereoselective methylation, conjugate addition and gold-catalyzed C–H insertion from the readily accessed cyclopentenone. Further work to access

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• better effectiveness than other tested supramolecular hosts. Keywords: cyclodextrin; dimer; methylation; solubilization; tetracene; Introduction Cyclodextrins (CDs) are cyclic oligomers of glucose that play an important role in supramolecular chemistry [1]. The structure of any CD contains a

• substituted rims are partially methylated CDs. Methylation reduces the formation of intramolecular hydrogen bonds, enhancing CDs water solubility, and also extends the hydrophobic cavity, thus improving its binding potential. A substantial increase of binding constant (K) for per-6-methylated CD compared to

• native CD was described, but an order of magnitude decrease of K was found for permethylated CD [2]. Also, methylation changes the solubility of CDs in organic solvents, expanding their potential field of application. CDs form the most stable complexes with hydrophobic compounds in polar solvents such as

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• deprotection of the silyl group was accomplished in the presence of potassium carbonate (K2CO3) and methanol to provide the terminal alkyne 5 in 96% yield in two steps. The iodoarene 8 [12][16] was facilely synthesized from sesamol (6) via methylation and iodination in an overall yield of 67%. With the

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

• -catalyzed cross-coupling reactions, such as arylation reactions catalyzed by Pd2(dba)3/CuI, as well as allylation and methylation reactions catalyzed by CuI⋅PPh3. C3-Benzyldimethylsilyl-appended furfurals are thus introduced as versatile platforms, providing a modular access to 3-substituted 2-furyl

• 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

• activation by alkoxides did not prove useful, C3–Si bond functionalization is achieved from benzyldimethylsilyl units upon siloxane formation in the presence of TBAF. Protocols for fluoride-promoted Pd/Cu-catalyzed arylation, as well as Cu-catalyzed allylation and methylation, have been developed. Overall

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

• chemicals, agrochemicals, pharmaceuticals and dyes [1][2][3][4]. Traditional methods for the preparation of N-methylamines involve the direct methylation of amines by using methyl halides [5][6][7], dimethyl sulfate [8], diazomethane [9], methyl triflate [10][11] or dimethyl carbonate [12][13][14][15] as

• 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

Isolation and biosynthesis of daturamycins from Streptomyces sp. KIB-H1544

• Yin Chen,
• Jinqiu Ren,
• Ruimin Yang,
• Jie Li,
• Sheng-Xiong Huang and
• Yijun Yan

Beilstein J. Org. Chem. 2022, 18, 1009–1016, doi:10.3762/bjoc.18.101

• condensation between two molecules of α-keto acid. Structurally diverse p-terphenyls are formed from these key intermediates by several tailoring reactions such as cyclization, tautomerization, methylation, and glycosylation. A previous study has shown that the formation of 2,5-diarylcyclopentenone proceeds

• -H1544 (Figure 3B). First, two molecules of phenylpyruvic acid (7), which is deaminated from ʟ-phenylalanine, are condensed into the six-membered polyporic acid (8) catalyzed by DatA. Then, 8 converts to compounds 3, 4, 5, and 6 through methylation and oxidation. On the other hand, polyporic acid (8

• ) probably undergoes rearrangement, decarboxylation, methylation reaction, and further modification to generate compounds 1 and 2. Conclusion S. sp. KIB-H1544 was isolated from the rhizosphere soil of Datura stramonium L. Two novel diarylcyclopentenones daturamycins A and B and one new p-terphenyl

The stereochemical course of 2-methylisoborneol biosynthesis

• Binbin Gu,
• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 818–824, doi:10.3762/bjoc.18.82

• resulted in a biosynthetic model that includes the methylation of geranyl diphosphate (GPP) to 2-methyl-GPP (2-Me-GPP), followed by cyclization to compound 1 (Scheme 1A) [8]. This process involves the isomerization of 2-Me-GPP by allylic transposition of diphosphate to 2-methyllinalyl diphosphate (2-Me-LPP

• enzyme in incubation buffer. The result for (S)-2-Me-LPP without enzyme in incubation buffer was the same as in C) and is not shown. Biosynthesis of 2-MIB (1). A) Naturally observed pathway through methylation of GPP to 2-Me-GPP by GPPMT and cyclization to 1 by 2MIBS. B) Reconstituted pathway through

• methylation of DMAPP to 2-Me-IPP with a hypothetical MT, followed by coupling of DMAPP and 2-Me-IPP to 2-Me-GPP by FPPS and cyclization to 1 by 2MIBS. Synthesis of (R)- and (S)-2-Me-LPP. Hypothetical mechanism for the isomerization of (S)-2-Me-LPP through 2-Me-GPP to (R)-2-Me-LPP. Supporting Information

New synthesis of a late-stage tetracyclic key intermediate of lumateperone

• Mátyás Milen,
• Bálint Nyulasi,
• Tamás Nagy,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66

• to the hydrazine derivative 4, followed by a Fischer indole synthesis with ethyl 4-oxopiperidine-1-carboxylate (5) provided tetracyclic compound 6. Its reduction with sodium cyanoborohydride in trifluoroacetic acid (TFA) to cis-indoline derivative (±)-7, followed by N-methylation [(±)-8] and

• reaction steps [8][9][10], e.g., because of the use of chloroacetamide instead of N-methylchloroacetamide, necessitating an additional N-methylation. The tetracycle 8 was finally subjected to the same reaction sequence as the corresponding racemate (see also Scheme 1), lumateperone (1) was thus prepared

• , which would have been based on the 1-methyl-4-amino-1,2,3,4-tetrahydroquinoxaline (23) intermediate (Scheme 4). We planned to convert the latter into (±)-9a via compound 22a by known methods. The synthesis of compound 23 was attempted as follows. N-Methylation of quinoxaline (24) with methyl p

A study of the photochemical behavior of terarylenes containing allomaltol and pyrazole fragments

• Constantine V. Milyutin,
• Andrey N. Komogortsev,
• Boris V. Lichitsky and
• Valeriya G. Melekhina

Beilstein J. Org. Chem. 2022, 18, 588–596, doi:10.3762/bjoc.18.61

• Discussion The starting pyrazoles 12 containing the 3-hydroxypyran-4-one fragment were obtained by a literature method [33]. The methoxy derivative 16 was synthesized by methylation of the corresponding pyrazole 12a according to the standard procedure [24][26] (Scheme 2). Initially, based on the previously

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

• ]. Macrocycle (S)-61, featuring two iodotriazole units, was reacted with bis-iodoalkyne 62 and azides 63a/b in order to establish the mechanical bond in an active metal template approach (using the conformational flexibility of the iodotriazole groups for copper N-ligation). Subsequent N-methylation of the

• the thread (see Figure 16). The stereoselective binding of chiral anions by rotaxanes 64a/b was studied by 1H NMR titration experiments, using the dicationic macrocycle (S)-61-Me22+ (obtained by methylation of the triazole units in (S)-61) as a reference system. As guest molecules, the Boc-protected

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

• -methyl-1,4-dimethoxynaphthalene, the construction of the naphthoquinone ring, the methylation of 1,4-naphthoquinone, and the electrochemical synthesis from 2-methyl-1,4-dihydroxynaphthalene. The works discussed in this section are grouped according to the synthetic approach that was employed to prepare

• dichloromethane and tert-butyl hydroperoxide at 80 °C (Table 2, entry 12). Methylation of 1,4-naphthoquinone Another route to prepare menadione (10) involves the methylation of 1,4-naphthoquinone. Because of their electron-deficient character, quinones are highly reactive with nucleophilic radicals [75]. The most

• -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

Amamistatins isolated from Nocardia altamirensis

• Till Steinmetz,
• Wolf Hiller and
• Markus Nett

Beilstein J. Org. Chem. 2022, 18, 360–367, doi:10.3762/bjoc.18.40

• -type siderophores. Structurally, compounds 1–5 are closely related to formobactin [10], brasilibactin [23], nocardimicin [24], and terpenibactins [15]. While the core scaffold of these natural products is conserved, they differ in the length of their fatty acid residues, their methylation pattern, and

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

• Jiang-Song Zhai and
• Da-Ming Du

Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3

• oxidized to compound 4 with m-chloroperbenzoic acid under mild conditions, and compound 4 can basically maintain the original excellent stereoselectivity (Scheme 5a). Meanwhile, we are pleased that methylation of 3ah took place easily to afford product 5 in 95% chemical yield with 99% ee and >20:1 dr under

Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents

• Rodolfo H. V. Nishimura,
• Thiago dos Santos,
• Valter E. Murie,
• Luciana C. Furtado,
• Leticia V. Costa-Lotufo and
• Giuliano C. Clososki

Beilstein J. Org. Chem. 2021, 17, 2968–2975, doi:10.3762/bjoc.17.206

• N-methylation [15]. The microwave-mediated reaction of 4-chloro-6-halo-2-phenylquinazolines 8a or 8b with o-toluidine (14a) in THF/H2O could be accomplished within 2 h and afforded the corresponding quinazoline derivatives 15a and 15b in 74% and 78% isolated yields, respectively. In addition, when

• and 8b. Conditions: a) NBS, CH3CN, 30 min, 25 °C; b) H2O, H2O2, I2, 24 h, 50 °C. N-Arylation reactions using ortho-, meta-, and para-substituted primary anilines of type 14 followed by methylation of ortho-derivatives 15a–d, to obtain the desired 4-anilinoquinazolines of type 10. N-Arylation reactions

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• subsequent ring-contracting α-ketol rearrangement would form 89. From here, a series of oxidation, cyclization, methylation, and/or reduction steps yield 92 and 93 (each representing two isolated products, one with R = Me and the other with R = Et). Oxidation at C1 and α-ketol rearrangement to 91, on the

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

• cofactor for methyl group transfer resulting in cytosine methylation. This recently discovered riboswitch-ribozyme activity opens new avenues for the development of RNA labeling tools based on tailored O6-alkylated preQ1 derivatives. Here, we report a robust synthesis for this class of pyrrolo[2,3-d

• scaffold. Keywords: deazapurines; heterocycles; pyrrolopyrimidines; queuosine; RNA cofactors; RNA methylation; Introduction Methylated preQ1 has attracted much attention recently because this compound has been found to function as cofactor for the conserved fold of a non-coding RNA, namely the preQ1

• class-I riboswitch [1]. This riboswitch acts as a ribozyme by using 7-aminomethyl-O6-methyl-7-deazaguanine (m6preQ1) as methyl group donor; it catalyzes self-methylation of a specific cytidine in the aptamer binding pocket, yielding N3-methyl cytidine (m3C) under release of 7-aminomethyl-7-deazaguanine

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

• methylation of C–H bonds because it would provide a convenient access to structures that might not otherwise be available for biological testing [89][90][91]. Hence, Doyle and co-workers realized an elegant approach for the methylation of (hetero)aryl chlorides 8 using trimethyl orthoformate as a methyl

• cycle involving the generation of methyl radicals via β-scission of a tertiary radical which in turn was generated from trimethyl orthoformate by a photogenerated chlorine radical-mediated HAT process (Figure 14) [92]. Recently, Stahl devised a photoredox nickel-catalyzed methylation of benzylic and α

• . Proposed catalytic cycle for the nickel/photoredox-catalyzed methylation of (hetero)aryl chlorides using trimethyl orthoformate. Proposed mechanism for the photoredox nickel-catalyzed hydroalkylation of internal alkynes. Proposed mechanism for the photoredox nickel-catalyzed acylation of α-amino C(sp3)–H