IBD-mediated oxidative cyclization of pyrimidinylhydrazones and concurrent Dimroth rearrangement: Synthesis of [1,2,4]triazolo[1,5-c]pyrimidine derivatives

• Caifei Tang,
• Zhiming Li and
• Quanrui Wang

Beilstein J. Org. Chem. 2013, 9, 2629–2634, doi:10.3762/bjoc.9.298

• ]pyrimidines by the oxidative cyclisation of benzothieno[2,3-d]pyrimidine hydrazones. The investigation has also suggested the important ability as inhibitors of Shiga toxin trafficking for protecting HeLa cells [9]. The wide range of biological activities shown by various triazolopyrimidines encouraged

• an efficient synthesis of new [1,2,4]triazolo[1,5-c]pyrimidine derivatives from hypervalent iodine (IBD)-mediated oxidative cyclisation of aldehyde pyrimidinylhydrazones and consecutive Dimroth rearrangement in relatively good yields under very mild conditions. Results and Discussion The

• feasible oxidative cyclisation to afford novel triazolopyrimidines. We initiated our investigation by examining the oxidative cyclization of 4a with iodobenzenediacetate (IBD) as an oxidant (Table 2). Thus, 4a was treated with one equivalent of freshly prepared IBD in dichloromethane at room temperature

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

• -methylpiperidine (1.21) using zeolites and easily aromatised by catalytic dehydrogenation to 3-picoline in 78% overall yield (Scheme 4) [26]. The overall processing sequence is highly energy-efficient (coupling of the endothermic cyclisation with the exothermic dehydration gives a reasonable energy balance). In

• addition the ammonia liberated during the cyclisation step is later consumed in the ammoxidation of the 3-picoline to the corresponding 3-cyanopyridine (Scheme 3). The value of substituted 3-picoline precursors is illustrated in the synthesis of clarinex (1.22, Desloratadine, Scheme 5), a dual antagonist

• the pyridine ring therefore yielding the corresponding piperidine 2.63. A base-mediated Dieckmann cyclisation and Krapcho decarboxylation [77] then furnishes 2.60. Traditionally, the reduction of 2.60 to prepare 2.59 can be carried out under fairly mild hydrogenation conditions that ultimately produce

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• ′-carbonyldiimidazole (CDI). In the first step the amidoxime is O-acylated with the activated derivative in a condensation reaction. The O-acylated amidoxime can be isolated or it can immediately undergo the cyclisation to the heterocyclic oxadiazole ring. This cyclodehydration reaction takes place by heating to

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• ) carboxamides. Results and Discussion Synthesis The synthesis of the required tetramic acid systems 2a–g (Scheme 1), 2h (Scheme 2) and 3a–f (Scheme 3) was achieved by Dieckmann cyclisation of the required N-alkyl-N-malonyl glycine (readily prepared from glycine). A similar strategy for the base-mediated

• cyclisation of N-acetoacetylamino acid esters leading to 3-acetyltetramates has been reported, which give N–H rather than N-alkyl systems [15][16][17]. Tetramate 7 was obtained from amino acid 6, except that the key intermediate 5 was obtained by reductive amination (Scheme 2) of (R)-citronellal (4), which

• generality [20][21]. We found that an approach based upon direct acylation of methyl thioethers 8a,b (these were readily obtained from the required N-acylmethionine by DCC/DMAP coupling with Meldrum’s acid and cyclisation under reflux) was possible, which made use of the high acidity of the tetramate system

Gold(I)-catalysed one-pot synthesis of chromans using allylic alcohols and phenols

• Eloi Coutant,
• Paul C. Young,
• Graeme Barker and
• Ai-Lan Lee

Beilstein J. Org. Chem. 2013, 9, 1797–1806, doi:10.3762/bjoc.9.209

• structural motifs found in a variety of important biologically active natural products such as vitamin E and flavanoids [1][2][3][4][5]. One approach towards chromans [6][7][8][9][10][11][12], which is biosynthetically inspired, is the Friedel–Crafts allylation [13] of phenols followed by cyclisation of the

• necessary to force the in situ cyclisation of 9 to 8. Next, lower equivalents of phenol 5 were investigated. Unfortunately, dropping the equivalents of phenol also appears to be detrimental to chroman formation: only Friedel–Crafts products 9 and 10 are observed with 2 or 1 equivalents of phenol (Table 1

• (Table 3, entries 7 and 8). Substitution at the β-position, however, is not tolerated: the reaction stops at the Friedel–Crafts stage (9t), and is reluctant to undergo further cyclisation to the desired chroman (Table 3, entry 9). Having investigated a series of tertiary allylic alcohols in entries 1–9

Computational study of the rate constants and free energies of intramolecular radical addition to substituted anilines

• Andreas Gansäuer,
• Meriam Seddiqzai,
• Tobias Dahmen,
• Rebecca Sure and
• Stefan Grimme

Beilstein J. Org. Chem. 2013, 9, 1620–1629, doi:10.3762/bjoc.9.185

• −1) and the B3LYP geometries (10.67 kcal mol−1). The total influence of the geometries and vibrations on ΔG‡ is therefore small (0.1–0.2 kcal mol−1 at most) and this technical detail cannot explain the discrepancy of the CCSD(T) barrier and the experimental value. The 5-exo cyclisation of 5-hexenyl

Development of an additive-controlled, SmI₂-mediated stereoselective sequence: Telescoped spirocyclisation, lactone reduction and Peterson elimination

• Brice Sautier,
• Karl D. Collins and
• David J. Procter

Beilstein J. Org. Chem. 2013, 9, 1443–1447, doi:10.3762/bjoc.9.163

• to “switch on” individual steps mediated by the electron transfer reagent. The sequence involves the use of two activated SmI2 reagent systems and a silicon stereocontrol element that exerts complete diastereocontrol over the cyclisation and is removed during the final stage of the sequence by

• Peterson elimination. The approach allows functionalised cyclopentanols containing two vicinal quaternary stereocentres to be conveniently prepared from simple starting materials. Keywords: cyclisation; free radical; Peterson elimination; reduction; samarium; telescoped process; Introduction Samarium

• manuscript, we report studies on SmI2-mediated cyclisation and lactone reduction that culminate in a “telescoped” sequence, i.e., a sequence of steps carried out on a single reaction mixture by the sequential addition of various reagents. In the sequence, additives are used with SmI2 to “switch on

Anionic cascade reactions. One-pot assembly of (Z)-chloro-exo-methylenetetrahydrofurans from β-hydroxyketones

• István E. Markó and
• Florian T. Schevenels

Beilstein J. Org. Chem. 2013, 9, 1319–1325, doi:10.3762/bjoc.9.148

• addition of 9 then affords the intermediate 10, which undergoes a 5-exo-dig cyclisation, ultimately yielding the observed (Z)-chloro-exo-methylenetetrahydrofuran 6. This structural motif constitutes the core of several biologically active compounds, including antimicrobial agents, fungicides and

Interplay of ortho- with spiro-cyclisation during iminyl radical closures onto arenes and heteroarenes

• Roy T. McBurney and
• John C. Walton

Beilstein J. Org. Chem. 2013, 9, 1083–1092, doi:10.3762/bjoc.9.120

• spectroscopy. Iminyls with suitably placed arene or heteroarene acceptors underwent cyclisations yielding phenanthridine-type products from ortho-additions. For benzofuran and benzothiophene acceptors, spiro-cyclisation predominated at low temperatures, but thermodynamic control ensured ortho-products

• , benzofuro- or benzothieno-isoquinolines, formed at higher temperatures. Estimates by steady-state kinetic EPR established that iminyl radical cyclisations onto aromatics took place about an order of magnitude more slowly than prototypical C-centred radicals. The cyclisation energetics were investigated by

• DFT computations, which gave insights into factors influencing the two cyclisation modes. Keywords: cyclisation; EPR spectroscopy; free radicals; heterocycles; oxime carbonates; Introduction Radical cyclisations onto aromatic acceptors take place readily, even though disruption of the 6π-electron

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• illustration is provided by the central transformation in the total synthesis of (–)-dendrobine (4), where the carbamyl radical cyclisation is followed by rupture of the cyclobutane ring [8][9]. This operation, displayed in Scheme 1, starts with benzoate 1 and results in the formation of the carbon–nitrogen

• quaternary centres. The chlorine atom in 8 is deliberately introduced in order to direct the second cyclisation towards the 6-endo mode. The chloride in intermediate 9 is now aliphatic and not vinylic as in precursor 8; it is therefore more susceptible to attack by stannyl radicals and the addition of an

• extra equivalent of tributylstannane ensures its in situ reductive removal. This domino radical cyclisation represents, in fact, a general strategy for the construction of indolizidines and pyrrolizidines, which constitute the core structure of numerous alkaloids. For pyrrolizidines, one needs simply to

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• reaction of chiral imines with enolates derived from Weinreb amides [13][14]. In previous work on the asymmetric synthesis of 2,6-disubstituted piperidines by C–N bond formation, we demonstrated that intramolecular aza-Michael ”type” cyclisation [15] using a β'-carbamate-α,β-unsaturated ketone

Alkyne hydroarylation with Au N-heterocyclic carbene catalysts

• Cristina Tubaro,
• Marco Baron,
• Andrea Biffis and
• Marino Basato

Beilstein J. Org. Chem. 2013, 9, 246–253, doi:10.3762/bjoc.9.29

• selectivity compared to the previously published complex AuCl(PPh3). Preliminary results on intramolecular hydroarylations using this catalytic system indicate, however, that alkyne hydration by traces of water may become a serious competing reaction. Keywords: alkyne; C–H functionalization; cyclisation

• ]. In such reactions, often simply termed cyclisation reactions, the arene and the alkyne are linked through a tether, the nature of which can range from simple alkyl groups to ether, amino, ester or amido groups; depending on the nature and length of the tether, different kinds of unsaturated poly

• the use of gold species as catalysts for alkyne hydroarylation is still quite limited. A substantial number of reports on the intramolecular cyclisation of arenes with tethered alkyne moieties using gold(I) or, to a lesser extent, gold(III) catalysts can be found in the literature [35][36][37][38][39

Radical zinc-atom-transfer-based carbozincation of haloalkynes with dialkylzincs

• Fabrice Chemla,
• Florian Dulong,
• Franck Ferreira and
• Alejandro Pérez-Luna

Beilstein J. Org. Chem. 2013, 9, 236–245, doi:10.3762/bjoc.9.28

• consistent with our anticipated zinc atom radical transfer mechanism (Scheme 1) and can be rationalized according to the following scenario (Scheme 5). The process involves the initial 1,4-addition of radical R to the starting enoate and the subsequent 5-exo-dig cyclisation of enoxy radical 14 to provide α

Reactions of salicylaldehyde and enolates or their equivalents: versatile synthetic routes to chromane derivatives

• Ishmael B. Masesane and
• Zelalem Yibralign Desta

Beilstein J. Org. Chem. 2012, 8, 2166–2175, doi:10.3762/bjoc.8.244

• temperature to give chalcone 14. To set the stage for the cyclisation reaction, the trans carbon–carbon double bond must either be isomerized to the cis form or completely reduced. In this case, chalcone 14 was treated with H2 in the presence of a catalytic amount of Pd to give intermediate 15 in 99% yield

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

Hybrid super electron donors – preparation and reactivity

• Jean Garnier,
• Douglas W. Thomson,
• Shengze Zhou,
• Phillip I. Jolly,
• Leonard E. A. Berlouis and
• John A. Murphy

Beilstein J. Org. Chem. 2012, 8, 994–1002, doi:10.3762/bjoc.8.112

• to an iodoarene; single electron transfer would afford an aryl radical that would undergo cyclisation efficiently [17], while two-electron transfer to afford an aryl anion would afford an aryl anion that would not cyclise in DMF as solvent [18]. The reaction with 30 was conducted under slightly

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

• Kieron M. G. O’Connell,
• Monica Díaz-Gavilán,
• Warren R. J. D. Galloway and
• David R. Spring

Beilstein J. Org. Chem. 2012, 8, 850–860, doi:10.3762/bjoc.8.95

• reactivity of four N-Boc-aminoalkenes containing α,β-unsaturated ester groups (1–4, Scheme 1), as substrates for intramolecular pairing reactions. The N-Boc protecting group was chosen to give the potential for deprotection to be carried out in tandem with the Lewis acid catalysed cyclisation reactions by

• chloroacetamide with thiourea gave the free amine [21], which was then protected with Boc anhydride. Finally, cross metathesis with ethyl acrylate furnished the desired compound 4 in 24% overall yield. Cyclisation reactions The first attempts at the tandem Boc-deprotection/bicyclisation of these substrates were

• mixture of diastereomers. The cyclisation of 1 gave pyrrolizidine 5 as a mixture of 4,10-trans-7,10-trans (trans-5) (42%) and 4,10-cis-7,10-trans (cis-5) (28%) isomers, which proved to be separable by flash chromatography. The stereochemistry of cis-5 was confirmed by analogy to known 1H and 13C NMR

Carbohydrate-auxiliary assisted preparation of enantiopure 1,2-oxazine derivatives and aminopolyols

• Marcin Jasiński,
• Dieter Lentz and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2012, 8, 662–674, doi:10.3762/bjoc.8.74

• hydroxylated 2H-1,2-oxazine derivatives is presented utilizing the [3 + 3] cyclisation of lithiated alkoxyallenes and an L-erythrose-derived N-glycosyl nitrone as precursors. This key step proceeded only with moderate diastereoselectivity, but allowed entry into both enantiomeric series of the resulting 3,6

• ][8], these nitrones very often furnish the corresponding products in a highly selective manner. In this context, reactions of lithiated alkoxyallenes with enantiopure nitrones are particularly of interest since they lead by a [3 + 3] cyclisation process to 1,2-oxazine derivatives with excellent

• were not isolated, but (in the presence of a drying agent) they underwent slow cyclisation in Et2O solution at room temperature to furnish the desired 1,2-oxazine derivative as a mixture of separable diastereomers (3S)-3a and (3R)-3a in 25% and 8% yield, respectively (Table 1, entry 3). The 1,2

Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

• Pavol Jakubec,
• Dane M. Cockfield,
• Madeleine Helliwell,
• James Raftery and
• Darren J. Dixon

Beilstein J. Org. Chem. 2012, 8, 567–578, doi:10.3762/bjoc.8.64

• targets has led to considerable interest from the synthetic community [12][13][14][15][16][17][18][19]. Common synthetic approaches to incorporate this motif include nucleophilic additions to pyridine rings and further manipulation [20][21][22][23][24][25], intramolecular iminium ion cyclisation [26][27

• [60], in the construction of architecturally complex polycyclic alkaloid structures [61] and more recently as a key complexity building step in the total synthesis of nakadomarin A [62][63][64][65]. Herein we wish to report our full findings in this synthetically powerful cyclisation cascade. The

• , however, was not supported by the low diastereoselectivity in the formation of 2j, in which presumably the relatively fast irreversible cyclisation outcompetes the equilibration processes. Considering the relatively broad range of imines and Michael adducts involved in the stereoselective cascade, we

Intramolecular carbenoid ylide forming reactions of 2-diazo-3-keto-4-phthalimidocarboxylic esters derived from methionine and cysteine

• Marc Enßle,
• Stefan Buck,
• Roland Werz and
• Gerhard Maas

Beilstein J. Org. Chem. 2012, 8, 433–440, doi:10.3762/bjoc.8.49

• not accomplished through the carbenoid route, but rather by cyclisation of a diazonium ion followed by deprotonation of the resulting sulfonium ion (Scheme 2) [17]. A diazoketone such as 3 has the structural prerequisites to undergo two types of intramolecular carbenoid ylide-forming reactions

• , reflux, 2 h; 2. N2=CHCO2Et (2 equiv), rt, 4 days. Rh(II)-catalysed carbenoid reactions of diazoesters 8a,b. Endo transition state for [3 + 3]-dimerisation of carbonyl ylide 14. Rh(II)-catalysed carbenoid reactions of diazoester 8c. Tandem cyclisation/intermolecular cycloaddition of diazoester 8a

Syntheses and applications of furanyl-functionalised 2,2’:6’,2’’-terpyridines

• Jérôme Husson and
• Michael Knorr

Beilstein J. Org. Chem. 2012, 8, 379–389, doi:10.3762/bjoc.8.41

• interesting to note that this cyclisation can lead to the formation of two different isomers [29][30], namely U- and S-shaped terpyridines 27, 28 (Figure 2). The ratio between both isomers is solvent dependent (Table 1). In all of the above-mentioned examples, symmetric terpyridines were prepared

A ferrocene redox-active triazolium macrocycle that binds and senses chloride

• Nicholas G. White and
• Paul D. Beer

Beilstein J. Org. Chem. 2012, 8, 246–252, doi:10.3762/bjoc.8.25

• investigate its anion binding and electrochemical-sensing properties. Results and Discussion Synthesis The CuAAC reaction of ferrocene bis(azide) 1 [12], with a large excess of 1,6-heptadiyne afforded 2 in 50% yield. An intramolecular Eglinton cyclisation reaction was used to prepare the ferrocene bis

Improved syntheses of high hole mobility phthalocyanines: A case of steric assistance in the cyclo-oligomerisation of phthalonitriles

• Daniel J. Tate,
• Rémi Anémian,
• Richard J. Bushby,
• Suwat Nanan,
• Stuart L. Warriner and
• and Benjamin J. Whitaker

Beilstein J. Org. Chem. 2012, 8, 120–128, doi:10.3762/bjoc.8.14

• the bulk of the alkyl substituents in the “ortho” positions will reinforce the preference for a (Z)-configuration about all of the exocyclic carbon/nitrogen partial double bonds, all six of which need to be Z in the cyclisation transition state. Hence, since the substituents would restrict the

• conformational space available to the intermediate, they would favour cyclisation. This phenomenon is clearly related to the effect of gem-dimethyl groups on the cyclisation of acyclic compounds (the Thorpe–Ingold effect) [37]. From the standpoint of making phthlocyanine-based liquid crystals, its importance is

• aromatic core [47]. The steric assistance provided to the base-initiated cyclisation of α-alkylated phthalonitriles, when the α-substituents are branched-chain, enables the corresponding metal-free phthalocyanines to be made easily and on a multigram scale. Although in the examples given in this paper the

Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy

• Iain Coldham,
• Adam J. M. Burrell,
• Hélène D. S. Guerrand,
• Luke Watson,
• Nathaniel G. Martin and
• Niall Oram

Beilstein J. Org. Chem. 2012, 8, 107–111, doi:10.3762/bjoc.8.11

• the ring junction positions are unsubstituted. Problems with conducting the cascade condensation, cyclisation, cycloaddition chemistry using azomethine ylides derived from enolisable aldehyde substrates [21] has been circumvented by incorporating a one-carbon unit at the alpha-position of the aldehyde

Manganese dioxide mediated one-pot synthesis of methyl 9H-pyrido[3,4-b]indole-1-carboxylate: Concise synthesis of alangiobussinine

• Jessica Baiget,
• Sabin Llona-Minguez,
• Stuart Lang,
• Simon P. MacKay,
• Colin J. Suckling and
• Oliver B. Sutcliffe

Beilstein J. Org. Chem. 2011, 7, 1407–1411, doi:10.3762/bjoc.7.164

• analogues containing the carboline heterocyclic moiety. A manganese dioxide mediated one-pot method starting with an activated alcohol and consisting of alcohol oxidation, Pictet–Spengler cyclisation, and oxidative aromatisation, offers a convenient process that allows access to β-carbolines. This one-pot