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

Continuous gas/liquid–liquid/liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination

• Jessica R. Breen,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• Jonathan Fray and
• Bhairavi Patel

Beilstein J. Org. Chem. 2011, 7, 1048–1054, doi:10.3762/bjoc.7.120

• hydrazine derivative. Water and ethanol are miscible with acetonitrile, thus enabling the cyclisation process to occur by efficient mixing of the two flow streams within the reactor channel. Similarly, fluoropyrazole derivatives 4b and 4c were prepared by reaction of 1a with fluorine and methyl hydrazine 3b

• derivatives were synthesised by sequential direct fluorination of appropriate 1,3-diketones and subsequent cyclisation of the in situ generated fluorodiketone with a hydrazine derivative. This represents the first example of a sequential, continuous flow gas/liquid–liquid/liquid process involving direct

Isotopic labelling studies for a gold-catalysed skeletal rearrangement of alkynyl aziridines

• Paul W. Davies,
• Nicolas Martin and
• Neil Spencer

Beilstein J. Org. Chem. 2011, 7, 839–846, doi:10.3762/bjoc.7.96

• the two isotopomers showed that a greater proportion of the 2,4-isomer formed from Path III was observed than with the other cyclisation precursors (Supporting Information File 1). Additionally, none of the 2,5-disubstituted pyrrole isomer, which would also result from B, was formed. In keeping with

• the deuterium labelling study using Ph3PAuCl/AgOTf. Supporting Information Supporting Information contains full experimental details for the preparation of the cyclisation precursors and their subsequent reactions. NMR spectra for the labelling studies are provided. Supporting Information File 74

Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

• Václav Jurčík,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2011, 7, 759–766, doi:10.3762/bjoc.7.86

• -(trifluoromethyl)acrylic acid (2) which offered a commercially available source of the CF3 group. It was envisaged that conjugate addition of an enantiomerically pure amide such as (R)- or (S)-3 would generate the addition adducts, carboxylate salts 4, as a mixture of diastereoisomers. Cyclisation to the N

• nitrate (CAN) oxidation offered a milder deprotection method [15]. The aza-Michael reaction proved straightforward to generate 4b and then cyclisation again using thionyl chloride and triethylamine gave β-lactams 5b in a 40% de, presumably again a thermodynamically biased isomer ratio. The

• is reported which took advantage of an aza-Michael addition between (S)-α-(p-methoxyphenyl)ethylamine (3b) and α-(trifluoromethyl)acrylic acid (2). Cyclisation and then chromatographic resolution of the β-lactam diastereoisomers 5b, followed by deprotection with ceric ammonium nitrate generated the β

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• thioacetate in toluene proceeds faster at 55 °C (Scheme 4). The synthesis of the unnatural enantiomer of the natural product spirobrassinin has been achieved by substitution at a quaternary centre by a sulfur nucleophile [14]. Intramolecular cyclisation of a dithiocarbamate 13 allows isolation of 14 with

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• cyclisation. However, this problem could be avoided by using an acid-labile oxalate protected hydrazine 104 as depicted in Scheme 23. The yield of this step can be further improved up to 84% if the corresponding calcium oxalate is used. The Bischler–Möhlau reaction is an alternative indole synthesis employing

• established which gave the desired product in 90% overall yield (Scheme 33). Alternatively, glycine can be reacted with methyl pentanimidate 169 to form the corresponding amidine 171 in high yield. Cyclisation, followed by a Vilsmeier-type reaction then furnishes the key chloroimidazolyl building block 172 in

• . Alternatively, in order to circumvent the regioselectivity issue, other pyrazole syntheses have been used. For example, the substituted aryl hydrazine 237 can be reacted with trifluoromethyl butynone in a one pot reaction. A Michael addition/cyclisation sequence renders only the desired regioisomer of the

Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation

• Vladimir N. Boiko

Beilstein J. Org. Chem. 2010, 6, 880–921, doi:10.3762/bjoc.6.88

9,10-Dioxa-1,2-diaza-anthracene derivatives from tetrafluoropyridazine

• Graham Pattison,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• John A. Christopher and
• David D. Miller

Beilstein J. Org. Chem. 2010, 6, No. 45, doi:10.3762/bjoc.6.45

• phenoxide, to give intermediate 5a. At this point, we would expect cyclisation to occur at position 5 to give product 6, again by analogy to the outcome of reaction between 3 and excess phenoxide. However, since nucleophilic aromatic substitution reactions are frequently reversible [13], conversion of 6