Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• -catalyzed aziridination of styrene (22) by chloramine-T (23, NaCl=NTs) as a source of nitrene in acetonitrile (Figure 5) [40]. No aziridine product was formed either without any source of copper or in the presence of a different copper salt, such as CuCl, CuCl2·2H2O, or CuOTf. Calix[4]pyrrole itself is

• conditions (catalyst/TBACl/aziridine 1:5:100 and 1.2 CO2 MPa at 125 °C) [71]. Out of all the used macrocycles, the unsubstituted H2TPP (18)/TBACl system turned out to be the best, giving up to 95% yield for the both N-alkyl/arylaziridine substrates with regioisomeric ratios up to 95:5 (70b:71b) for R = n-Bu

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• derived from the interaction of non-activated alkenes with thianthrene [24]. This procedure has the advantage of separating the oxidative activation of the alkenes from the aziridination step, allowing efficient access to a variety of aziridine building blocks containing sensitive functional groups. This

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• solvent, resulted in a 16% yield of 3a (Table 1, entry 7). Performing aziridination with 10 equivalents of HFIP in CH2Cl2 resulted in a 38% yield (Table 1, entry 8). The aziridine product 3a was not observed when other Lewis or Brønsted acids, such as BF3·Et2O, TfOH, or Zn(OTf)2, were employed in CH2Cl2

• unprotected alcohol is tolerated in our procedure, with product 3l delivered at 50% NMR yield; 3l is sensitive to column chromatography, and thus aziridine-opening to a cyclic ether was observed (31% isolated yield) during purification. Aziridination of cis- or trans-4-octene afforded aziridine 3m as a 1.3

• :1.0 trans/cis mixture in 72% and 64% yield, respectively. While many styrene derivatives polymerize in HFIP [44], 1,2-disubstituted styrene derivatives were sufficiently stable to engage in the developed aziridination reaction, with cis- or trans-β-methylstyrene 1n furnishing aziridine 3n as

Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

• Wenqing Hao,
• Long Wang,
• Jinlei Zhang,
• Dawei Teng and
• Guorui Cao

Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29

• 4aa [35] was isolated in 62% yield (Scheme 4). On the basis of the transformation of 3aa to 4aa, a tentative reaction mechanism is proposed. As shown in Scheme 5, the spiropyridazine-benzosultam 3aa was firstly oxidized to intermediate A. Next, an aziridine was formed with the hydrolysis of the amide

Enabling artificial photosynthesis systems with molecular recycling: A review of photo- and electrochemical methods for regenerating organic sacrificial electron donors

• Grace A. Lowe

Beilstein J. Org. Chem. 2023, 19, 1198–1215, doi:10.3762/bjoc.19.88

Efficient synthesis of aziridinecyclooctanediol and 3-aminocyclooctanetriol

• Emine Salamci and
• Ayse Kilic Lafzi

Beilstein J. Org. Chem. 2022, 18, 1539–1543, doi:10.3762/bjoc.18.163

• versatility in numerous regio- and stereoselective ring opening and/or expansion reactions, as well as rearrangements [5]. The aziridine structural motif is present in natural products such as mitomycins and azinomycins (Figure 1) [1][5], which exhibit potent biological activities such as antitumor and

• antibiotic activities. Therefore, synthetic methodologies for the preparation of the aziridinyl system have attracted attention in recent decades. Opening of the aziridine ring by using different nucleophiles gives the corresponding amino alcohols, amino esters, azido amines, amines, and other derivatives [9

• ]. Furthermore, aziridine derivatives are valuable precursors for the synthesis of aminocyclitols, which can be found in nature in several families of natural and clinically important antibiotics [10]. Aminocyclitols containing the amino alcohol motif are important structural components for modifying bioactive

Efficient synthesis of ethyl 2-(oxazolin-2-yl)alkanoates via ethoxycarbonylketene-induced electrophilic ring expansion of aziridines

• Yelong Lei and
• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 70–76, doi:10.3762/bjoc.18.6

• -2-yl)alkanamides and 1-(oxazolin-2-yl)alkylphosphonates. Keywords: aziridine; diazooxoester; diazo compound; ketene; oxazoline; ring expansion; Introduction Oxazoline derivatives are an important class of nitrogen and oxygen-containing five-membered unsaturated heterocycles [1] and widely exist in

• in the presence of electrophilic reagents [18][19] (Scheme 1d). Aziridines can be considered as the NCC structural fragment after ring-opening and have been applied in the synthesis of aziridine-imine-containing chiral tridentate ligands [20], 2-alkylideneoxazolidines [21], and N-vinylamides [22]. We

• Discussion The reaction of ethyl 2-diazo-3-oxobutanoate (1a) and 2-phenylaziridine (2a) was first selected as a model reaction to optimize the reaction conditions (Table 1). Diazo ester 1a (0.36 mmol) and aziridine 2a (0.3 mmol) in 1,2-dichloroethane (DCE, 1 mL) were heated at 110 °C for 30 min with

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

Allylic alcohols and amines by carbenoid eliminative cross-coupling using epoxides or aziridines

• Matthew J. Fleming and
• David M. Hodgson

Beilstein J. Org. Chem. 2021, 17, 2385–2389, doi:10.3762/bjoc.17.155

• to (unlithiated) epoxide 5 and was formed quantitatively (dr = 57:43) if the LTMP was omitted. Analogous chemistry to that described above (Scheme 3 and Scheme 4) was found to be possible with a terminal aziridine 17, providing access to the corresponding N-Bus-protected allylic amines 18 [19] and 19

• (Scheme 8). In these cases, the amines are formed by preferential β-elimination [20][21] of lithium methoxide rather than BusNLi2. Synthesis of cyclopropylidene 21 (Scheme 9), suggests a terminal N-Bus-aziridine is capable of being deprotonated by the α-lithio cyclopropane from stannane 11; this contrasts

• . Alongside the cinnamylamine 23, small amounts of the aziridine-derived carbenoid dimerisation product, 2-ene-1,4-diamine 24 [5], were observed. While the reaction profile was not altered on a solvent switch to hexane (23 (62%, E/Z = 61:39); 24 (16%)), the yield of cinnamylamine 23 was slightly improved in

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

• -bound chloride anion performs a SN2-type attack on the coordinated benzoyl-protected aziridine, which leads to a formal addition of HCl. This concept was further developed and successfully employed by Ooi in the desymmetrization of meso-aziridines 32 with TMSX as chloride and bromide with similar

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

• important tool in the asymmetric synthesis of aziridines [25][26], α-amino acids [27][28], β-amino acids [23][29] and branched α-amines [30][31]. The Darzens-type asymmetric synthesis of N-(p-toluenesulfinyl)aziridine 2-carboxylate esters (7 and 8) was described through the addition of lithium α

• -bromoenolates to enantiopure p-toluenesulfinamide 5. cis-aziridine 7a was formed as the major diastereoisomer in 89% yield and the trans-isomer in 8% yield in a one-step procedure using lithium enolates of methyl bromoacetate 6a and sulfinyl imine 5. Lithium enolates of methyl α-bromopropionate gave trans

• -aziridine in 50% yield under the same conditions. The transition state is proposed with a six-membered chair-like transition containing a four-membered metallocycle. In cis-aziridine the enolate of methyl α-bromoacetate has E-geometry and the trans-aziridine 8a has Z-geometry [32][33]. In the transition

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• ring-opening followed by an intramolecular substitution to afford chiral thietane 175 [61]. 2.2.6 Synthesis via the nucleophilic ring-opening of three-membered heterocycles and subsequent displacement from aziridine-2-methyl tosylate: (1R,2S,6R)-6-Methyl-7-tosyl-7-azabicyclo[4.1.0]heptan-2-yl tosylate

• (179) is a derivative of aziridine-2-methyl tosylate. After the ring-opening with ammonium tetrathiomolybdate and subsequent intramolecular cyclization, the compound was converted into a bridged thietane 183 in 75% yield. The results indicated that, in the ring-opening step, tetrathiomolybdate

• nucleophilically attacked the more substituted aziridine carbon atom [62] (Scheme 37). The thioetherification cyclization of 1,3-dihaloalkanes, 3-haloalkyl sulfonates, or disulfonates of alkane-1,3-diols with sodium sulfide is a common method for the preparation of thietanes. However, this method is suitable for

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

•  29). 2.4. Fluorodehydroxylation of β-hydroxyphenylalanine Alternatively, Kollonitach et al. prepared racemic 3-fluorophenylalanine (136) through the fluorodehydroxylation of 3-hydroxyphenylalanine (137) using sulfur tetrafluoride (SF4) in HF [67] (Scheme 30). 2.5. Ring opening of aziridine

• -hydroxyphenylalanine (137). Synthesis of β-fluorophenylalanine from aziridine derivatives. Synthesis of β-fluorophenylalanine 136 via direct fluorination of pyruvate esters. Synthesis of β-fluorophenylalanine via fluorination of ethyl 3-phenylpyruvate enol using DAST. Synthesis of β-fluorophenylalanine derivatives

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• in equilibrium with a spectator bis-nitrene species 19 and proceeded through styrene 20 insertion, followed by ring closure and release of the aziridine. Interestingly, this otherwise classical mechanism is enabled by the accessibility of doublet and quadruplet states close in energy and this

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

• -position on the ring could be accessed. A dual catalytic cycle was proposed, where the Cu–Si species formed in situ undergoes transmetallation to the Pd(II) species resulting from the attack of Pd(0) on the aziridine ring, ultimately affording the silylated product with silicon at the benzylic site (Scheme

Asymmetric synthesis of CF₂-functionalized aziridines by combined strong Brønsted acid catalysis

• Xing-Fa Tan,
• Fa-Guang Zhang and
• Jun-An Ma

Beilstein J. Org. Chem. 2020, 16, 638–644, doi:10.3762/bjoc.16.60

• may bring about a complementary catalytic platform. Encouragingly, the targeted CF2-functionalized aziridine 4a was obtained in up to 51% ee and high diastereoselectivity, albeit in a low yield (Table 1, entries 1 and 2). The difficulty in further improving the conversions might be ascribed to the

• dr values, including alkyl or halogen-substituted phenyl and 2-naphthyl ketones (Scheme 2). Unfortunately, phenylglyoxal monohydrates bearing strong electron-withdrawing groups were not compatible with the current conditions. X-ray analysis of aziridine 4a confirmed the absolute configuration of the

• chiral centers, pointing at a cis-aziridination process [46]. Scaled-up experiments with model substrate 1a also proved to be feasible, delivering the chiral CF2-aziridine 4a with comparable results (Scheme 3a). The 4-methoxyphenyl group of 4a was cleaved smoothly with ceric ammonium nitrate, giving the

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• cationic polyene cyclization, transition-metal- or photocatalyst-mediated radical polyene cyclization [72]. The key to such transformation is to install a proper initiator within the substrate such as an allylic alcohol, an acetal, an aziridine, an N-acetal, a hydroxylactam, or a 1,3-dicarbonyl moiety. van

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

• racemization, alternative three-carbon chirons would be of great value in enantioselective syntheses of natural compounds and/or drugs. This review article summarizes applications of N-(1-phenylethyl)aziridine-2-carboxylates, -carbaldehydes and -methanols in syntheses of approved drugs and potential

• efficiency of a 2-substituted N-(1-phenylethyl)aziridine framework as chiron bearing a chiral auxiliary. Keywords: alkaloids; amino acids; asymmetric synthesis; ceramides; chiral catalysis; chiral pool; N-(1-phenylethyl)aziridine chiron; sphingoids; Introduction The synthesis of enantiomerically pure

• which is finally easily removed [11]. Among three-carbon chirons related to Garner’s aldehyde derivatives of N-(1-phenylethyl)aziridine-2-carboxylic acid 5–8 (Figure 2) play an important role in asymmetric synthesis as they function as a chiral synthon combined with a chiral auxiliary [(R)- or (S)-1

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• bond for steric reasons. Selective removal of the silyl protective group allowed for the hydroxymethyl to carboxyl transformation to (4S,5R)-26, and hydrolysis afforded (2S,3R)-2 as the hydrochloride (Scheme 6) [55]. From homochiral aziridine An interesting approach to protected (2S,3R)-2 makes use of

• the aziridine (2R,1′S)-27 as a synthetic equivalent of L-serine (Scheme 7) [56]. Stereoselective reduction of ketone (2R,1′S)-28 gave hydroxyaziridine 29 as the major (10:1) product which, after the protection of the hydroxy group, was subjected to the regioselective aziridine ring opening, catalytic

• give dimethyl ester 98 (Scheme 25). Silver oxide-promoted methylation introduces a MeO-C4 unit. Regioselective aziridine ring opening in 99 was then carried out in the known way with benzyl alcohol or methanol to produce substituted dimethyl L-glutamates 100 and 101. To ensure clean deprotection in the

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• -trifluoromethylation has been extended to several other substrates. Starting from N-(aryl)- and N-(benzyl)allylamines 16, the reaction affords β-benzoyloxy-β’-trifluoromethylamines 17 through the formation of an aziridine intermediate (Scheme 7) [40]. The latter was further utilized to give access to a variety of β

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• the aziridine intermediate 3 was stable and could be isolated when the reaction was carried out in non-polar solvents. In particular, 2-(halomethyl)oxazoles 6 are a class of compounds rather underexplored, even though they are frequently key intermediates in the total synthesis of natural products [30

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence

• Attila Márió Remete,
• Melinda Nonn,
• Santos Fustero,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2017, 13, 2364–2371, doi:10.3762/bjoc.13.233

• cyclopentane β-amino ester (±)-6 with Deoxofluor under various conditions provided an unidentifiable mixture of products. However, the reaction of diol (±)-6 with 1.5 equiv of Deoxofluor in the presence of DBU as the base furnished aziridine derivative (±)-7 within 10 min through intramolecular cyclization via

• the carbamate N-atom (Scheme 3). Again, only the selective transformation of the C-3 hydroxy group with the fluorinating agent took place, without the involvement of the C-4 OH group. Unfortunately, all further attempted fluorinations of hydroxylated aziridine (±)-7 under various conditions using for

• contrast, when using the fluorinating reagent in excess, both hydroxy groups are converted to leaving groups to afford intermediate T15. The latter affords aziridinium ion T16 through intramolecular reaction with the amide nitrogen. The subsequent aziridine-ring opening by reaction with fluoride results in

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• - and Z-1b, and depending on the substitution pattern of the aziridine ring, the formation of the pyrrolidine derivative 34 occurred either with complete stereoselectivity or mixtures of isomeric products were obtained. The [3 + 2]-cycloaddition of the azomethine ylide E,Z-32a, formed via conrotatory

• ring opening of aziridine cis-33a, with E-1b yielded cycloadduct 34a exclusively through a concerted mechanism [38] (Scheme 10). In contrast, a more complex reaction of cis-1-methyl-2,3-diphenylaziridine (cis-33b) with both E- and Z-1b led to a mixture of stereoisomeric cycloadducts 34b. The same

• experimental results were rationalized by a computational study performed at the DFT B3LYP/6-31G(d) level of theory with the PCM solvation model [39]. The thermal [3 + 2]-cycloadditions of azomethine ylides derived from diethyl cis- and trans-1-(4-methoxyphenyl)aziridine-2,3-dicarboxylates with E-1b led to

Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

• Emilia S. Streng,
• Darren S. Lee,
• Michael W. George and
• Martyn Poliakoff

Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

• be expected from the intramolecular closure of 8, consistent with the results observed with bromoalkylamines [48], and suggesting the rate of closure for three-membered rings is slower than that of five- and six-membered rings. We cannot rule out the formation of aziridine as an intermediate in the

• five- (4) and seven-membered ring (6), three-membered aziridine rings were not detected. Competing N- and O-alkylation was observed at higher temperatures with ethanolamine (8) and 6-amino-1-hexanol (5), suggesting ring closure is slower in these cases. Ethanolamine (8) produced dimers as the major

Self-optimisation and model-based design of experiments for developing a C–H activation flow process

• Alexander Echtermeyer,
• Yehia Amar,
• Jacek Zakrzewski and
• Alexei Lapkin

Beilstein J. Org. Chem. 2017, 13, 150–163, doi:10.3762/bjoc.13.18

• resulting in the formation of an aziridine 2 (Scheme 1) [19]. The reaction was recently discovered [20] and its mechanism studied [21] and later proven [18]. A simplified mechanism is shown in Scheme 2. In the reaction of interest, the starting material 1, an aliphatic secondary amine, is converted into an

• aziridine product 2 [19][20]. Orange rings show C–H and C–N bonds in the substrate and the product, respectively, indicating the location of the C–H activation. A simplified reaction mechanism based on literature [21], showing intermediate B and the side reaction compounds 1∙HOAc and A. The key step