Facile approach to N,O,S-heteropentacycles via condensation of sterically crowded 3H-phenoxazin-3-one with ortho-substituted anilines

• Eugeny Ivakhnenko,
• Vasily Malay,
• Pavel Knyazev,
• Nikita Merezhko,
• Nadezhda Makarova,
• Oleg Demidov,
• Gennady Borodkin,
• Andrey Starikov and
• Vladimir Minkin

Beilstein J. Org. Chem. 2024, 20, 336–345, doi:10.3762/bjoc.20.34

• ) possible. By using a similar procedure to that applied to the synthesis of compounds 4, we succeeded in the preparation of 14Н-quinoxaline[2,3-b]phenoxazine derivatives 5 (Scheme 3). The nitrogen atoms in the oxazine and pyrazine rings of 5, N(7), N(12), and N(14), offer three possible positions for the N

One-pot nucleophilic substitution–double click reactions of biazides leading to functionalized bis(1,2,3-triazole) derivatives

• Hans-Ulrich Reissig and
• Fei Yu

Beilstein J. Org. Chem. 2023, 19, 1399–1407, doi:10.3762/bjoc.19.101

• carbohydrate mimetics, but the reductive cleavage of the 1,2-oxazine rings to aminopyran moieties did not proceed cleanly with these compounds. Keywords: alkynes; azides; copper catalysis; nucleophilic substitution; 1,2-oxazines; Introduction The concept of click reactions [1][2], in particular, the

• good yields and furnished another set of multivalent carbohydrate mimetics [48][49][50]. In the current report, we want to disclose our experience with an “inverted” approach to multivalent systems [51]: bicyclic 1,2-oxazine derivatives of type G [52][53], which can be regarded as internally protected

• several times by our group with good success for reductive ring-openings of 1,2-oxazine derivatives [63][64]. A slight excess of samarium diiodide in tetrahydrofuran completely consumed compound 21 within five hours. Compound 26 was isolated in 50% yield, but again the sample was not clean. The NMR data

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• –O bond from an 1,2-oxazine, itself obtained by a nitroso Diels–Alder reaction from a chiral nitroso derivative and a functionalized diene (Figure 3). The nitroso Diels–Alder cycloaddition reaction has been well studied and has been used as a powerful tool for synthesis [19][20][21][22]. We have

• /z): [M + H]+ calcd 407.2377; found, 407.2359. (6R)-tert-Butyl 5-(diethoxyphosphoryloxy)-6-(2-((triisopropylsilyl)oxy)ethyl)-3,6-dihydro-2H-1,2-oxazine-2-carboxylate (10b): A solution of the enol phosphate 17 (420 mg, 1.03 mmol) in chloroform (1.8 mL) was added to a solution of the Wightman reagent 6

Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

• Ákos Bajtel,
• Mounir Raji,
• Matti Haukka,
• Ferenc Fülöp and
• Zsolt Szakonyi

Beilstein J. Org. Chem. 2021, 17, 983–990, doi:10.3762/bjoc.17.80

• conditions (Scheme 6). The proposed reaction pathway for the ring–ring tautomerism of 21A and 21B is presented in Figure 4 and it explains why the acidic environment (present generally in CDCl3 solution) is necessary. In a similar manner, an oxazolidine–1,3-oxazine tautomerism of pulegone-based 3-amino-1,2

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• give analogue 7b reduced the lipophilicity. Interestingly, while the nonfluorinated 7a and 7c diastereomers have different logD7.4 values, this is not the case for their fluorinated analogues 7b and 7d. Oxazine derivative 8 featured in the development of centrally active β-secretase (BACE1) inhibitors

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

• -unsaturated oxime an unusual six-membered oxazine 133h was reported as the major product [133]. A similar cyclization of oximes 134 with the introduction of an azido group was carried out using TMSN3 as an azide source (Scheme 45) [134]. The reaction is applicable for β,γ-unsaturated oximes having both aryl

Cation-induced ring-opening and oxidation reaction of photoreluctant spirooxazine–quinolizinium conjugates

• Phil M. Pithan,
• Sören Steup and
• Heiko Ihmels

Beilstein J. Org. Chem. 2020, 16, 904–916, doi:10.3762/bjoc.16.82

• behavior as it can undergo isomerization and cyclization reactions. For example, the irradiation of a 5’-naphthylvinyl-substituted spirooxazine derivative led not only to a ring opening of the oxazine unit but also to an irreversible loss of the photochromic properties, resulting from a cyclization

• -Trimethylspiro[indoline-2,3'-naphtho[2,1-b][1,4]oxazine]-5'-yl)vinyl)quinolizinium tetrafluoroborate (3a) [60][62][64][65]: To a solution of 2-methylquinolizinium tetrafluoroborate (2a, 116 mg, 500 µmol) and the 5’-formyl-substituted spirooxazine 1b (214 mg, 600 µmol) in MeCN (15 mL) was added piperidine (42.6

• . (E)-8-(2-(1,3,3-Trimethylspiro[indoline-2,3'-naphtho[2,1-b][1,4]oxazine]-5'-yl)vinyl)coralyne tetrafluoroborate (3b) [60][62][64][65]: To a suspension of coralyne tetrafluoroborate (2b, 90.2 mg, 200 µmol) and the 5’-formyl-substituted spirooxazine 1b (143 mg, 400 µmol) in MeCN (6 mL) was added

Probing of local polarity in poly(methyl methacrylate) with the charge transfer transition in Nile red

• Aydan Yadigarli,
• Qimeng Song,
• Sergey I. Druzhinin and
• Holger Schönherr

Beilstein J. Org. Chem. 2019, 15, 2552–2562, doi:10.3762/bjoc.15.248

• films on a glass support was probed by the energy of the charge transfer transition in the oxazine dye Nile red (NR) at 25 °C. The absorption and fluorescence spectra of NR were observed to shift to the red with increasing solvent polarity, because of the intramolecular charge transfer character of the

• NR molecules in the ground state and slow sub-glass transition (Tg) relaxations in PMMA. Keywords: charge transfer; dipole moment; fluorescence; inhomogeneous broadening; oxazine dye; polarity probe; polymer permittivity; Introduction The chain and segment mobility as well as the permittivity of

• [1] and segment mobilities inferred [13], respectively. For other purposes the oxazine tracer dye Nile red (NR, Figure 1) served as a local probe to enable the study of degradation of enzyme labile polymersomes [14]. The same dye has been reported as probe for local permittivity in polymers, in

Unprecedented nucleophile-promoted 1,7-S or Se shift reactions under Pummerer reaction conditions of 4-alkenyl-3-sulfinylmethylpyrroles

• Takashi Go,
• Akane Morimatsu,
• Hiroaki Wasada,
• Genzoh Tanabe,
• Osamu Muraoka,
• Yoshiharu Sawada and
• Mitsuhiro Yoshimatsu

Beilstein J. Org. Chem. 2018, 14, 2722–2729, doi:10.3762/bjoc.14.250

• -bromobenzenesulfonyl derivative, which was expected to act as a good substrate for the isolation of crystals, and performed the same sequential process of sulfanyl-1,6-diynes to the oxazine derivatives (Scheme 7). Hydroamination–cyclisation of diyne 1 with N-allyl-p-bromobenzenesulfonamide 3g and the successive

• cyclisation afforded 25g with a 56% yield. We obtained the 4H-pyrrolo[3,4-g]oxazine derivative as crystals. The structure of these products was determined through NMR spectroscopy experiments (COSY and HMBC data are reported and discussed in Supporting Information File 1). Conclusion We found unique 1,7-S and

• . Proposed mechanism. Crossover experiment. Lewis acid-catalysed cyclization of diols. Sequential process of sulfanyl-1,6-diyne 1 to 4H-pyrrolo[3,4-g]oxazine 25g. Screening the reaction conditions for the Pummerer reactions. DFT Calculation of the two pathways: from 14 to 15x or from 14 to 21x. Supporting

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• ]oxazine-2,4(1H)-dione (9b). A 500 mL single neck round-bottomed flask equipped with a football-shaped PTFE stirring bar (16 mm × 37 mm) was charged with 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol, 1.0 equiv) followed by the addition of tetrahydrofuran (230 mL, 0.2 molar) and solid triphosgene (13.7 g

Metal-free formal synthesis of phenoxazine

• Gabriella Kervefors,
• Antonia Becker,
• Chandan Dey and
• Berit Olofsson

Beilstein J. Org. Chem. 2018, 14, 1491–1497, doi:10.3762/bjoc.14.126

• , unusually stable iodine(III) intermediate in the O-arylation was observed by NMR and could be converted to the product upon longer reaction time. Keywords: arylation; cyclization; diaryl ether; diaryliodonium salt; phenol; Introduction Phenoxazine (1) is a tricyclic compound consisting of an oxazine ring

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• ortho-amidoalkylation of phenols in which a tandem Knoevenagel condensation occurs through o-QM followed by the formation of an unstable oxazine intermediate [64]. Later, the same research group published a similar reaction extended by various lactams carried out in trifluoroacetic acid in water [65

Oxidative cycloaddition of hydroxamic acids with dienes or guaiacols mediated by iodine(III) reagents

• Hisato Shimizu,
• Akira Yoshimura,
• Keiichi Noguchi,
• Victor N. Nemykin,
• Viktor V. Zhdankin and
• Akio Saito

Beilstein J. Org. Chem. 2018, 14, 531–536, doi:10.3762/bjoc.14.39

• test this hypothesis, the oxazine 3aa was treated with TfOH in DCM at 40 °C for 18 h and afforded 4 quantitatively. Furthermore, the TfOH-mediated formation of nitrone from such HDA adducts has been reported [23]. It should be mentioned that the structures of 3aa and 4 were determined by single crystal

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

• alcoholic groups in positions 4 and 5, oxazine derivative (±)-9 was formed as the single product through intramolecular cyclization involving the nucleophilic amide O-atom (Scheme 4). Upon treatment of diol (±)-8 with excess Deoxofluor (4 equiv), in addition to the expected fluorinated oxazine (±)-10, a

• of the alcoholic group at C-4 in (±)-8 into a leaving group, an intramolecular cyclization takes place to afford oxazine (±)-9. Subsequently, this oxazine, in the presence of an excess Deoxofluor gives fluorinated derivative (±)-10. Finally, in the presence of fluoride as base, deprotonation (T9

• ), followed by oxazine-ring opening through olefinic-bond migration (T10) then gives the highly conjugated amino acid ester (±)-11 (Scheme 5). Noteworthy, the presence of DBU in the experiment of (±)-8 with Deoxofluor did not have a significant effect on the ratio of the products. However, in the presence of

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

• -bromooxime 26 with lithium enolate 27 to give oxime 28 via the Michael addition to transient nitrosoalkene NSA6 [31]. Oxime adduct 28 existed predominantly in a cyclic 1,2-oxazine form (Scheme 11). Subsequent benzylation of oxime 28 and the thermal retro-[2 + 2]/[4 + 2]-cycloaddition cascade followed by

Iodination of carbohydrate-derived 1,2-oxazines to enantiopure 5-iodo-3,6-dihydro-2H-1,2-oxazines and subsequent palladium-catalyzed cross-coupling reactions

• Michal Medvecký,
• Igor Linder,
• Luise Schefzig,
• Hans-Ulrich Reissig and
• Reinhold Zimmer

Beilstein J. Org. Chem. 2016, 12, 2898–2905, doi:10.3762/bjoc.12.289

• pyridine in DMF furnished 5-iodo-substituted 1,2-oxazine derivatives 4 with high efficacy. The alkenyl iodide moiety of 1,2-oxazine derivatives syn-4 and anti-4 was subsequently exploited for the introduction of new functionalities at the C-5 position by applying palladium-catalyzed carbon–carbon bond

• -forming reactions such as Sonogashira, Heck, or Suzuki coupling reactions as well as a cyanation reaction. These cross-coupling reactions led to a series of 5-alkynyl-, 5-alkenyl-, 5-aryl- and 5-cyano-substituted 1,2-oxazine derivatives being of considerable interest for further synthetic elaborations

• focused our interest on the so far unknown functionalization at the C-5 position of the synthetically useful enantiopure 3,6-dihydro-1,2-oxazines 3. Herein, we now disclose our results on the iodination of 3 to provide the previously undescribed 5-iodo-1,2-oxazine derivatives 4. These new intermediates

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• , Czech Republic Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA 10.3762/bjoc.12.184 Abstract The hetero-Diels–Alder reaction between a nitroso dienophile and a conjugated diene to give the 3,6-dihydro-2H-1,2-oxazine scaffold is useful for the synthesis of

• many biologically interesting molecules due to the diverse opportunities created by subsequent transformations of the resulting 1,2-oxazine ring. This review discusses the rationale for the observed regio- and stereoselectivity and the methods developed in recent years used to control and improve the

• stereo- and regioselectivity for the synthesis of 1,2-oxazine scaffolds. Keywords: diene; hetero-Diels–Alder; nitroso compounds; regioselectivity; stereoselectivity; Review Introduction The hetero-Diels–Alder reaction represents one of the most important methods in organic synthesis, providing various

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• reaction providing oxazine derivatives 26, was reported by Ye and co-workers (Scheme 10) [21]. In this reaction, nucleophile 24 is coupled to arylenone 25 to give the desired product. Initially a Michael reaction is taking place, followed by cyclization. After screening of various acids, hydrobromic acid

• cycloalkanones using catalyst 11 [18]. The enantioselective synthesis of indolo- and benzoquinolidine compounds through aza-Diels–Alder reaction of enones with cyclic imines [19]. Enantioselective [5 + 2] cycloaddition [20]. Asymmetric synthesis of oxazine derivatives 26 [21]. Asymmetric synthesis of bicyclo

Azirinium ylides from α-diazoketones and 2H-azirines on the route to 2H-1,4-oxazines: three-membered ring opening vs 1,5-cyclization

• Nikolai V. Rostovskii,
• Mikhail S. Novikov,
• Alexander F. Khlebnikov,
• Galina L. Starova and
• Margarita S. Avdontseva

Beilstein J. Org. Chem. 2015, 11, 302–312, doi:10.3762/bjoc.11.35

• azadienes onto the keto group, provides a rapid access to non-fused 2H-1,4-oxazine-5-carboxylates 4, a new type of non-spirocyclic 1,4-oxazine photochromes [15]. In the search for new compounds with useful photochromic characteristics and a high fatigue resistance we focused on 5-unsubstituted, 5-aryl-, and

• at all. Our study of the chemical behavior of 2H-azirines under Rh(II)-catalyzed decomposition of diazoketones was started with searching for optimal conditions for the catalytic reaction of 2,3-diphenyl-2H-azirine (1a) with 1-diazo-1-phenylpropan-2-one (2a), leading to oxazine 4a. The most

• successful procedure involving addition of Rh2(OAc)4 to a boiling 1:1.25 mixture of azirine 1a and diazo compound 2a in 1,2-dichloroethane (DCE) (procedure A) gave rise to oxazine 4a and azadiene Z-3a in 60 and 7% yields, respectively (Scheme 2, Table 1, entry 1). It was also shown that azadiene Z-3a did not

Isoxazolium N-ylides and 1-oxa-5-azahexa-1,3,5-trienes on the way from isoxazoles to 2H-1,3-oxazines

• Alexander F. Khlebnikov,
• Mikhail S. Novikov,
• Yelizaveta G. Gorbunova,
• Ekaterina E. Galenko,
• Kirill I. Mikhailov,
• Viktoriia V. Pakalnis and
• Margarita S. Avdontceva

Beilstein J. Org. Chem. 2014, 10, 1896–1905, doi:10.3762/bjoc.10.197

• Manning [4][5] discovered the Rh-catalyzed reaction of diazo esters with 3,5-dialkylisoxazoles, benzo[d]isoxazole and 3-chlorobenzo[d]isothiazole leading to the corresponding 2H-1,3-oxazines, 2H-benzo[e][1,3]oxazine and 2H-benzo[e][1,3]thiazine. The authors assumed that the reaction of isoxazoles A with

• diazo esters B involved an isoxazolium N-ylide intermediate C formed by an attack of the rhodium carbenoid onto the isoxazole nitrogen. Furthermore, ylide C could undergo either a 1,2-shift to directly generate oxazine E or a ring opening to 1-oxa-5-azahexa-1,3,5-triene D, followed by a 6π

• -electrocyclization to give oxazine E (Scheme 1). At the same time, the third mechanism of the reaction, involving a one-step formation of 1-oxa-5-azahexa-1,3,5-triene D, cannot be excluded. The reaction of a carbenoid with isoxazoles is the only known one-step intermolecular reaction which can in principle produce

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• . Unnatural divalent rigid p-terphenyl-linked C-aryl glycosides with 2.0 nm dimension are available using Suzuki cross-couplings. The key compound, a p-bromophenyl-substituted 1,2-oxazine, was prepared by a stereoselective [3 + 3]-cyclization of a D-isoascorbic acid-derived (Z)-nitrone and lithiated TMSE

• -allene. The Lewis acid-induced rearrangement of this heterocycle provided the corresponding bicyclic 1,2-oxazine derivative that may be regarded as internally protected amino sugar analogue. After subsequent reduction of the carbonyl group, the resulting bicyclic compound was used for Suzuki cross

• bicyclic 1,2-oxazine derivative 3 was used as key building block for the Suzuki cross-coupling reaction to synthesize p-terphenyl-linked derivatives 1. The key intermediate 3 was prepared by a Lewis acid-induced rearrangement of 3,6-dihydro-2H-oxazine 4, that origins from a stereoselective [3 + 3

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• Rai in the synthesis of nucleoside analogs 111 and 112 bearing novel nucleobase derived from benzo[e][1,3]oxazine (Scheme 46) [123]. The developed reactions were much more effective than those examined on other inorganic supports (i.e., silica gel, neutral or basic alumina). The conversion of the

• sugar urea to the corresponding isocyanate intermediate, accompanied by the loss of ammonia, was postulated to be the key step of the reaction cascade. Another approach to nucleoside analogs bearing a nucleobase derived from benzo[e][1,3]oxazine was developed by Rai and Singh (Scheme 47) [124]. The

Magnesium bis(monoperoxyphthalate) hexahydrate as mild and efficient oxidant for the synthesis of selenones

• Andrea Temperini,
• Massimo Curini,
• Ornelio Rosati and
• Lucio Minuti

Beilstein J. Org. Chem. 2014, 10, 1267–1271, doi:10.3762/bjoc.10.127

• , the corresponding oxirane 3e in 77% yield, resembling the previously reported one by oxidation with MCPBA (73% [9]). The MMPP oxidation of β-benzoylamino phenyl selenide 1f in methanol afforded exclusively the 1,3-oxazine 3f in excellent yield (84%). This result is in accordance with data reported by

Synthesis of new enantiopure poly(hydroxy)aminooxepanes as building blocks for multivalent carbohydrate mimetics

• Léa Bouché,
• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 213–223, doi:10.3762/bjoc.10.17

• enantiopure nitrones and lithiated TMSE-allene we prepared three 1,2-oxazine derivatives which underwent a highly stereoselective Lewis acid-induced rearrangement to give bicyclic products in good yield. Subsequent reductive transformations delivered a library of new poly(hydroxy)aminooxepane derivatives. The

• crucial final palladium-catalyzed hydrogenolysis of the 1,2-oxazine moiety was optimized resulting in a reasonably efficient approach to a series of new seven-membered carbohydrate mimetics. Keywords: aminooxepanes; carbohydrate mimetics; hydrogenolyses; Lewis acid-induced; lithiated allenes; nitrones

• with excellent diastereoselectivities (Scheme 3). The nitrone 3 was used as a 96:4 mixture (with respect to the stereogenic center of the 1,3-dioxolane ring) and it could therefore provide four diasteromers of 1,2-oxazine syn-10 (two major syn- and two minor anti-diasteromeres), but only a single syn

Gold(I)-catalyzed enantioselective cycloaddition reactions

• Fernando López and
• José L. Mascareñas

Beilstein J. Org. Chem. 2013, 9, 2250–2264, doi:10.3762/bjoc.9.264

• -(1-alkynyl)-2-alken-1-ones 26 and nitrones. The reactions provide fused heterobicyclic oxazine derivatives of type 27 with good yields and excellent regio- and diastereoselectivities. The racemic series, promoted by Ph3PAuCl/AgOTf as a catalyst [84], was translated into an enantioselective version by