An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• methods utilising cycloadditions of electron-rich oxazoles and acrylates [17][18] tri- and tetrazines with alkenes/alkynes [19] or pyrones with nitriles [20] have been used successfully to access specifically functionalised pyridines which are difficult to prepare by the more direct condensation routes. A

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

• , aldol reactions, 1,3-dipolar cycloadditions, and cyclizations [13][14][15]. Other gold-promoted asymmetric induction strategies rely on the use of chiral counterions. Indeed, it has been shown that a tight chiral ion pair with the gold cation is able to induce excellent levels of asymmetry in certain

• , cycloadditions are atom economical, and usually take place with high levels of regio- and stereocontrol. Especially relevant in terms of synthetic practicality are cycloadditions which are catalyzed by transition metal complexes [19][20][21][22][23]. In particular, gold(I) complexes, owing to their high

• carbophilicity, low oxophilicity and high oxidation potential between gold(I) and gold(III) have shown a unique potential to unveil novel types of chemoselective and stereoselective cycloadditions involving alkynes, allenes or alkenes [24][25][26]. A lot of interest has been directed to the development of these

Microflow photochemistry: UVC-induced [2 + 2]-photoadditions to furanone in a microcapillary reactor

• Sylvestre Bachollet,
• Kimitada Terao,
• Shin Aida,
• Yasuhiro Nishiyama,
• Kiyomi Kakiuchi and
• Michael Oelgemöller

Beilstein J. Org. Chem. 2013, 9, 2015–2021, doi:10.3762/bjoc.9.237

• , Takayama-cho, Ikoma, Nara 630-0101, Japan 10.3762/bjoc.9.237 Abstract [2 + 2]-Cycloadditions of cyclopentene and 2,3-dimethylbut-2-ene to furanone were investigated under continuous-flow conditions. Irradiations were conducted in a FEP-microcapillary module which was placed in a Rayonet chamber

• smaller diameter, the light transmission in the microcapillary was still superior with 53%, compared to 0.3% in the test tube. [2 + 2]-Cycloadditions with cyclopentene The photoaddition of cyclopentene (2) to 1 was subsequently investigated in detail under batch and microflow conditions (Scheme 2, Table 1

• isolation of product 3 by column chromatography was also challenging as fractions had to be analyzed by material-consuming NMR spectroscopy. [2 + 2]-Cycloadditions with 2,3-dimethylbut-2-ene Subsequent cycloadditions were performed using 2,3-dimethylbut-2-ene (4) as a reagent (Scheme 3, Table 2) [39]. In

[3 + 2]-Cycloadditions of nitrile ylides after photoactivation of vinyl azides under flow conditions

• Stephan Cludius-Brandt,
• Lukas Kupracz and
• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1745–1750, doi:10.3762/bjoc.9.201

• azides 1 from alkenes 6 under flow conditions [9]. Schematic presentation of the flow set-up for the synthesis of 2H-azirines 2 under inductive heating (IH, left) and photochemical (hν, right) conditions. Photoinduced cycloadditions of vinyl azides 1a–f and electron-deficient alkenes 4a–d. All

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

• Sándor B. Ötvös,
• Ádám Georgiádes,
• István M. Mándity,
• Lóránd Kiss and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1508–1516, doi:10.3762/bjoc.9.172

• –alkyne cycloadditions. Gramm-scale CF synthesis of triazole 22 under conditions B. CF synthesis of 1,2,3-triazole-substituted alicyclic β-amino acid derivatives. Copper contents in the triazole products after column chromatographic purification on silica gel. Supporting Information Supporting

Dipolar addition to cyclic vinyl sulfones leading to dual conformation tricycles

• Steven S. Y. Wong,
• Michael G. Brant,
• Christopher Barr,
• Allen G. Oliver and
• Jeremy E. Wulff

Beilstein J. Org. Chem. 2013, 9, 1419–1425, doi:10.3762/bjoc.9.159

• coupling partners for these cycloadditions, and in many cases the reaction rate can be enhanced through the addition of a Lewis acid that can coordinate to the carbonyl function, thereby lowering the energy of the olefin LUMO. By contrast, vinyl sulfones (with the exception of simple aryl vinyl sulfone

• species [13][14][15][16][17][18][19][20][21]) have been less-frequently employed as acceptors in 1,3-dipolar cycloadditions [22][23][24][25]. Indeed, we are only aware of a single prior example of a cyclic alkyl vinyl sulfone participating in a dipolar addition with an azomethine ylide [26]. In part, this

• pathways are open to the reactants. The additional aromatic substituent in 7 (relative to 4) once again contributed to significant broadening in both the 1H and 13C NMR spectra. Conclusion Our results comprise the first syntheses of tricyclic sulfones by 1,3-dipolar cycloadditions of azomethine imines with

Thiourea-catalyzed Diels–Alder reaction of a naphthoquinone monoketal dienophile

• Carsten S. Kramer and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 1414–1418, doi:10.3762/bjoc.9.158

• carbenes, guanidines, thioureas, amidinium ions, diols, and Brønsted acids showed their value to give densely functionalized Diels–Alder products in high selectivities [1][2][3][4][5][6][7]. In addition, some organocatalysts enabled even the formation of quaternary centers in Diels–Alder cycloadditions [3

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

• Aleksey I. Gerasyuto,
• Zhi-Xiong Ma,
• Grant S. Buchanan and
• Richard P. Hsung

Beilstein J. Org. Chem. 2013, 9, 1170–1178, doi:10.3762/bjoc.9.131

• handled vinylogous amides and vinyl iminium salts. It provides a significant complementary, if not superior, approach to aza-[4 + 2] cycloadditions in constructing piperidines, because the aza-dienes and imines required are not always the most accessible and/or easily handled substrates given the problems

Synthesis of phenanthridines via palladium-catalyzed picolinamide-directed sequential C–H functionalization

• Ryan Pearson,
• Shuyu Zhang,
• Gang He,
• Nicola Edwards and
• Gong Chen

Beilstein J. Org. Chem. 2013, 9, 891–899, doi:10.3762/bjoc.9.102

• –Hubert condensation [9], radical-mediated reactions [10][11][12][13], metal-catalyzed cross-couplings [14][15][16][17][18], cycloadditions [19], and others [20][21][22]. More recently, methods based on the metal-catalyzed functionalization of carbon–hydrogen (C–H) bonds have also emerged as viable

Diastereoselective synthesis of nitroso acetals from (S,E)-γ-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or LiClO₄

• Leandro Lara de Carvalho,
• Robert Alan Burrow and
• Vera Lúcia Patrocinio Pereira

Beilstein J. Org. Chem. 2013, 9, 838–845, doi:10.3762/bjoc.9.96

• Materiais Inorgânicos, Universidade Federal de Santa Maria, 97105-900, Santa Maria, Rio Grande do Sul, RS, Brazil 10.3762/bjoc.9.96 Abstract Chiral nonracemic aminated nitroso acetals were synthesized via diastereoselective multicomponent [4 + 2]/[3 + 2] cycloadditions employing new (S,E)-γ-nitrogenated

• furnish cyclic nitronate derivatives of type 3 [1][3]. In particular, the reactivity of nitroalkenes with unactivated olefins has been extensively investigated by Denmark and co-workers in [4 + 2] hetero-Diels–Alder (HDA) cycloadditions [1][3] and, in some instances, the resulting cyclic nitronates such

• -dipolarophiles to furnish nitroso acetals of type 4 in an inter- or intramolecular fashion [1][2][3][8][9]. These nitroso acetals can be transformed into functionalized pyrrolizidin-3-ones and in sequence into alkaloid nuclei [1][3][10][11]. The majority of the tandem nitroalkene cycloadditions require the

A versatile and efficient approach for the synthesis of chiral 1,3-nitroamines and 1,3-diamines via conjugate addition to new (S,E)-γ-aminated nitroalkenes derived from L-α-amino acids

• Vera Lúcia Patrocinio Pereira,
• André Luiz da Silva Moura,
• Daniel Pais Pires Vieira,
• Leandro Lara de Carvalho,
• Eliz Regina Bueno Torres and
• Jeronimo da Silva Costa

Beilstein J. Org. Chem. 2013, 9, 832–837, doi:10.3762/bjoc.9.95

• nucleophiles [5][6][7][8][9][10], in Friedel–Crafts alkylations [11][12][13][14], and Baylis–Hillman reactions [15][16][17][18]. Furthermore, nitroalkenes can react as dipolarophiles in [3 + 2] cycloadditions [19][20][21][22], as dienophiles in [4 + 2] cycloadditions [23][24][25][26], and as heterodienes in

Caryolene-forming carbocation rearrangements

• Quynh Nhu N. Nguyen and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2013, 9, 323–331, doi:10.3762/bjoc.9.37

• a hydrogen-bridged minimum. Both mechanisms are predicted to involve concerted suprafacial/suprafacial [2 + 2] cycloadditions, whose asynchronicity allows them to avoid the constraints of orbital symmetry. Keywords: carbocation; cycloaddition; density functional theory; mechanism; reactive

Towards a biocompatible artificial lung: Covalent functionalization of poly(4-methylpent-1-ene) (TPX) with cRGD pentapeptide

• Lena Möller,
• Christian Hess,
• Jiří Paleček,
• Yi Su,
• Axel Haverich,
• Andreas Kirschning and
• Gerald Dräger

Beilstein J. Org. Chem. 2013, 9, 270–277, doi:10.3762/bjoc.9.33

• required for these kinds of 1,3-dipolar cycloadditions, but their potential cytotoxic properties limit the usability in biomedical applications [16][17]. For overcoming this problem, several copper-free ligation methods were developed. In this work we pursue both options, i.e., the copper-mediated as well

• , by the use of Huisgen-type “click” chemistry (Scheme 2). cRGD pentapeptide 1b was prepared in sufficient amounts by solution-phase chemistry [23]. Because of the disadvantage associated with copper-mediated 1,3-cycloadditions of alkynes with azides in biological or biomedical applications we

• cycloadditions, the model compound fluoresceinyl azide 9[29][30] was first coupled to TPX derivatives 7a or 7b, under identical conditions as described for cRGD peptide 1b. The resulting polymers 8c and 8d were studied by determining the UV absorption peaks of fluorescein between 400 and 600 nm (Figure 4

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• azide alkyne cycloadditions. In addition, the up-scaling of some particular azide-modified sugars is described. Keywords: click chemistry; glycans; peptoids; polyalkynes; polyamines; solid-phase chemistry; Introduction To date, oligosaccharides have gained more and more interest as potential drugs in

Flow photochemistry: Old light through new windows

• Jonathan P. Knowles,
• Luke D. Elliott and
• Kevin I. Booker-Milburn

Beilstein J. Org. Chem. 2012, 8, 2025–2052, doi:10.3762/bjoc.8.229

• years. This also presented an opportunity to compare different reactor types in areas such as selectivity, yield and productivity [22]. Review Microflow photochemistry Photocycloadditions Although many photocycloadditions have been performed by using other types of reactor, only [2 + 2] cycloadditions

• ) [26]. Asymmetric induction can be achieved in [2 + 2] cycloadditions through the use of a chiral auxilliary. The [2 + 2] reaction shown in Scheme 3 employed a chiral ester function to direct the facial selectivity of the addition of the enone to cyclopentene. Diastereoselectivity was found to be

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225

• steps (high step economy). Keywords: alicyclic; bisallenes; cyclic; cycloadditions; cycloisomerization; isomerization; molecular complexity; step economy; Table of Contents Introduction Review Acyclic conjugated bisallenes 1.1 Synthesis of hydrocarbons 1.2 Synthesis of functionalized systems 1.3

• the 2-azetidinone 113 carrying the 1,2,4,5-hexatetraen-3-yl substituent in the 4-position. The bisallene is a very good diene for Diels–Alder cycloadditions as will be discussed in Section 1.4.1. The unusual hexakis(ferrocenyl)-1,2,4,5-hexatetraene (116) is produced as one of many side-products when

• : “internally” 2 possesses a conjugated diene system and “externally” it displays two cumulated ones. For the case of cycloadditions (see below) this should allow for [2 + 4] (Diels–Alder) and [2 + 2]cycloadditions (additions to allenes, ketenes, etc.). As we shall see later, both modes of cycloadditions have

Asymmetric Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene

• Magnus Rueping and
• Sadiya Raja

Beilstein J. Org. Chem. 2012, 8, 1819–1824, doi:10.3762/bjoc.8.208

• diastereoselectivities under mild reaction conditions. The results reported not only show that chiral BINOL derived phosphoric acid diesters can be efficient catalysts for [4 + 2] cycloadditions involving less-electron-rich dienes but additionally demonstrate the high potential of these acidic Brønsted acids in

Copper-catalyzed CuAAC/intramolecular C–H arylation sequence: Synthesis of annulated 1,2,3-triazoles

• Rajkumar Jeyachandran,
• Harish Kumar Potukuchi and
• Lutz Ackermann

Beilstein J. Org. Chem. 2012, 8, 1771–1777, doi:10.3762/bjoc.8.202

• -economical syntheses of annulated 1,2,3-triazoles were accomplished through copper-catalyzed intramolecular direct arylations in sustainable one-pot reactions. Thus, catalyzed cascade reactions involving [3 + 2]-azide–alkyne cycloadditions (CuAAC) and C–H bond functionalizations provided direct access to

• consisting of copper(I)-catalyzed [3 + 2]-azide–alkyne cycloadditions (CuAAC) and intramolecular C–H bond arylations. Notably, the optimized copper catalyst accelerated two mechanistically distinct transformations, which set the stage for the formation of up to one C–C and three C–N bonds in a chemo- and

Iridium-catalyzed intramolecular [4 + 2] cycloadditions of alkynyl halides

• Andrew Tigchelaar and
• William Tam

Beilstein J. Org. Chem. 2012, 8, 1765–1770, doi:10.3762/bjoc.8.201

• Andrew Tigchelaar William Tam Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada N1G 2W1 10.3762/bjoc.8.201 Abstract Iridium-catalyzed intramolecular [4 + 2] cycloadditions of diene-tethered alkynyl

• –94%). These results are the first examples of cycloadditions of alkynyl halides using an iridium catalyst. Keywords: alkynyl halide; cycloaddition; diene-tethered alkyne; iridium; transition-metal catalyst; Introduction Iridium complexes have been used as catalysts for a wide variety of reactions

• , including homogeneous hydrogenation [1][2], C–H activation [3][4][5], asymmetric ring-opening reactions [6], and a variety of cycloisomerizations [7][8][9][10], and cycloadditions [11][12][13][14][15][16][17][18][19][20]. Traditionally these types of cycloisomerization and cycloaddition reactions are

Metal–ligand multiple bonds as frustrated Lewis pairs for C–H functionalization

• Matthew T. Whited

Beilstein J. Org. Chem. 2012, 8, 1554–1563, doi:10.3762/bjoc.8.177

• FLPs [35], Mδ+═Eδ− FLPs may also react with nonpolar unsaturated substrates, such as alkenes or alkynes, by polarizing the substrate to facilitate cycloaddition. [2 + 2] cycloadditions of Mδ+═Eδ− FLPs with alkenes/alkynes have been thoroughly explored in the context of olefin metathesis (where E = CR2

Approaches to α-amino acids via rearrangement to electron-deficient nitrogen: Beckmann and Hofmann rearrangements of appropriate carboxyl-protected substrates

• Sosale Chandrasekhar and
• V. Mohana Rao

Beilstein J. Org. Chem. 2012, 8, 1393–1399, doi:10.3762/bjoc.8.161

• be investigated (most notably the Strecker reaction) [2], but recent developments focus on cycloadditions [3], rare amino acids [4], chiral catalysis [5], etc. It is noteworthy, however, that two of the most widely applied methods for the introduction of the amine group – the Beckmann [6][7][8][9

Palladium-catalyzed substitution of (coumarinyl)methyl acetates with C-, N-, and S-nucleophiles

• Kalicharan Chattopadhyay,
• Erik Fenster,
• Alexander J. Grenning and
• Jon A. Tunge

Beilstein J. Org. Chem. 2012, 8, 1200–1207, doi:10.3762/bjoc.8.133

• ]. Due to the ambiphilic nature of the heterocyclic ring of coumarin, this core-structure undergoes a diverse array of coupling reactions, such as halogenations [25], cycloadditions [26][27][28][29][30][31][32], conjugate additions [33][34][35][36][37] and transition-metal-catalyzed C–H activation

Parallel solid-phase synthesis of diaryltriazoles

• Matthias Wrobel,
• Jeffrey Aubé and
• Burkhard König

Beilstein J. Org. Chem. 2012, 8, 1027–1036, doi:10.3762/bjoc.8.115

• predictability of their potency and selectivity as inhibitors is still limited. We have recently reported the synthesis of triazole-based α-helix mimetics 3 and 4 [16], which are efficiently available through azide–alkyne cycloadditions [17]. We now report the use of this chemistry to prepare libraries of

• –t and either copper or ruthenium-catalyzed [2 + 3] cycloadditions. The three reactions and the obtained products 11 (reaction 1), 12 (reaction 2) and 13 (reaction 3) are summarized in Table 2. Reaction 1 follows the established protocol and, gave after removal of the copper salts with a solution of

• , DMSO-d6). Compounds 13, with the exception of compound 13f, were only characterized by mass spectrometry during the synthesis of the compound library. The copper-mediated [2 + 3] cycloadditions are restricted to terminal alkynes. However, the ruthenium-catalysis allows the use of internal alkynes. In

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

• Hiroki Oguri,
• Haruki Mizoguchi,
• Hideaki Oikawa,
• Aki Ishiyama,
• Masato Iwatsuki,
• Kazuhiko Otoguro and
• Satoshi Ōmura

Beilstein J. Org. Chem. 2012, 8, 930–940, doi:10.3762/bjoc.8.105

• cycloadditions with the dipolarophiles installed at modules 3 and 4 leading to either tetracyclic 14 or hexacyclic 13. In this full account, we also employ a piperidine-based manifold 15 bearing an amino group in order to expand the applicability of the various building blocks in the four-step parallel synthesis

• scaffold. In addition, removal of the N-nosyl protecting group by treatment with benzenethiol led to 26b in quantitative yield [42]. To generate skeletal variations by altering the sites of the cycloadditions, we next synthesized a branched precursor 29 bearing a pair of identical indole units at modules 3

• the cycloadditions efficiently incorporated consecutive quaternary centers into the complex fused skeleton, overriding the considerable steric hindrance of the dipolarophiles composed of the tri- and even tetra-substituted olefin groups. To test the generality of the site-selective cycloaddition at

An intramolecular inverse electron demand Diels–Alder approach to annulated α-carbolines

• Zhiyuan Ma,
• Feng Ni,
• Grace H. C. Woo,
• Sie-Mun Lo,
• Philip M. Roveto,
• Scott E. Schaus and
• John K. Snyder

Beilstein J. Org. Chem. 2012, 8, 829–840, doi:10.3762/bjoc.8.93

• Intramolecular inverse electron demand cycloadditions of isatin-derived 1,2,4-triazines with acetylenic dienophiles tethered by amidations or transesterifications proceed in excellent yields to produce lactam- or lactone-fused α-carbolines. Beginning with various isatins and alkynyl dienophiles, a pilot-scale

• are also known [62][63][64]. In addition, cycloadditions of 3-vinyl-7-azaindole have also been used to close the pyridine ring [65], as have intramolecular dipolar cycloadditions of 2-azidoindole derivatives [66], and intramolecular cycloadditions of carbodiimides [67][68]. We had envisioned that a

• library of annulated α-carboline structures 6 could be prepared by the intramolecular inverse electron demand Diels–Alder reaction (IEDDA) of isatin-derived 1,2,4-triazines 7 with tethered electron-rich dienophiles (Scheme 1) [69]. Inverse electron demand Diels–Alder cycloadditions employing electron