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

• . Unless stated otherwise, all commercially available compounds (Acros, Fluka, Aldrich) were used as received. Ethyl 4-((tert-butyldimethylsilyl)oxy)-5,8-dimethoxy-2-methyl-10-oxo-4,4a,9a,10-tetrahydro-1H-spiro[anthracene-9,2'-[1,3]dioxolane]-9a-carboxylate (2a): In a small flask dienophile 3 (23.1 mg

A construction of 4,4-spirocyclic γ-lactams by tandem radical cyclization with carbon monoxide

• Mitsuhiro Ueda,
• Yoshitaka Uenoyama,
• Nozomi Terasoma,
• Shoko Doi,
• Shoji Kobayashi,
• Ilhyong Ryu and
• John A. Murphy

Beilstein J. Org. Chem. 2013, 9, 1340–1345, doi:10.3762/bjoc.9.151

• of this spiro structure is of continued interest for synthetic chemists. Recently, Comesse and Daïch reported the synthesis of 4,4-spirocyclic oxindole γ-lactams by tandem spirocyclization via nucleophilic halide displacement and amide coupling [4]. Shaw and co-workers reported the synthesis of 4,4

• -5-methoxyphenyl)-4-methylbenzenesulfonamide (1b) with CO gave the corresponding spiro lactam 2b in 53% yield (Table 1, entry 2). N-(2-(Azidomethyl)allyl)-N-(2-iodophenyl)methanesulfonamide (1c) showed a comparable reactivity with 1a and 1b (Table 1, entry 3). The reaction of 1-(2-(azidomethyl

• )allyloxy)-2-iodobenzene (1d) also gave the spiro benzofuran lactam 2d in 58% yield (Table 1, entry 4). On the other hand, 2-(azidomethyl)allyl(2-iodophenyl)sulfane (1e) gave a low yield of the corresponding spiro thiobenzofuran lactam (19%, Table 1, entry 5), which may be rationalized by the less effective

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

• derivatives [1][2]. Spiro-cyclisations in which tethered radicals add to the ipso-C-atoms of the rings are less common, although minor spiro-products not infrequently accompany the main ortho-ones in Pschorr syntheses [3][4][5]. Cyclisations onto arenes by N-centred radicals are rarer, but iminyl radical ArC

• attention. Iminyl cyclisations have also been utilised in natural-product syntheses [10][16][25][26]. Iminyl radical spiro-cyclisations onto aromatics have been reported in a few cases, and spiro-intermediates have occasionally been proposed in mechanistic explanations [15][18][27][28][29]. Although a

Facile synthesis of functionalized spiro[indoline-3,2'-oxiran]-2-ones by Darzens reaction

• Qin Fu and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 918–924, doi:10.3762/bjoc.9.105

• Qin Fu Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.9.105 Abstract A series of functionalized spiro[indoline-3,2'-oxiran]-2-ones was efficiently synthesized by Darzens reaction of phenacyl bromides with isatins both with N

• -alkyl groups and without N-substituent in the presence of potassium carbonate as a base catalyst. When two equivalents phenacyl bromides were used in the reaction, the N-substitution reaction of isatin also finished with the formation of spiro-oxirane-oxindoles. Keywords: Darzens reaction; isatin

• ; oxindole; oxirane; spiro-epoxyoxindole; spirooxindole; Introduction The spirooxindole unit is a privileged heterocyclic motif that forms the core structure of a large family of natural alkaloids and many pharmacological agents with important bioactivity and interesting structural properties [1][2][3][4][5

Synthesis of functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] via one-pot four-component reactions

• Li-Juan Zhang,
• Qun Wu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 846–851, doi:10.3762/bjoc.9.97

• malononitrile afforded the functionalized spiro[indoline-3,4’-pyridine] derivatives in good yields. Similar reactions with ethyl cyanoacetate successfully afforded the functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] as the main products according to the structures of the

• arylamines and other primary amines. Keywords: 1,4-dihydropyridine; electron-deficient alkyne; four-component reaction; isatin; one-pot reaction; spiro compound; Introduction β-Enaminones and β-enamino esters represent important synthetic building blocks for the development of versatile carbon–carbon bond

• [12][13][14][15][16][17][18][19][20][21][22][23]. Recently, Perumal and we have both developed an efficient synthetic procedure for functionalized spiro[indoline-3,4’-pyridines] by domino reactions of in situ generated β-enamino esters, isatin and malononitrile with triethylamine as the base catalyst

Synthesis of 2,3-dihydronaphtho[2,3-d][1,3]thiazole-4,9-diones and 2,3-dihydroanthra[2,3-d][1,3]thiazole-4,11-diones and novel ring contraction and fusion reaction of 3H-spiro[1,3-thiazole-2,1'-cyclohexanes] into 2,3,4,5-tetrahydro-1H-carbazole-6,11-diones

• Lidia S. Konstantinova,
• Kirill A. Lysov,
• Ljudmila I. Souvorova and
• Oleg A. Rakitin

Beilstein J. Org. Chem. 2013, 9, 577–584, doi:10.3762/bjoc.9.62

• reaction of anthracene-1,4-diones 4 led unexpectedly to the corresponding 2-thioxo-2,3-dihydroanthra[2,3-d][1,3]thiazole-4,11-diones 10. The reaction of 3H-spiro[1,3-thiazole-2,1'-cyclohexanes] 1d, 2d with Et3N in chlorobenzene under reflux yielded 2,3,4,5-tetrahydro-1H-carbazole-6,11-diones 15, 16, i.e

• formation of thiol 17 followed by the dihydropyrrole ring closure under the impact of both quinone and amine groups and the generation of the aromatic pyrrole cycle with hydrogen sulfide extrusion by the action of base (triethylamine). Although, to the best of our knowledge, the transformation of 3H-spiro

• -ethyldiisopropylamine in the reaction of 2-(methylamino)anthracene-1,4-diones with sulfur monochloride was discovered and explained. 3H-Spiro(thiazol-2,1'-cyclohexanes) underwent a new ring contraction and fusion reaction resulting in the formation of tetrahydroindoles. Experimental Melting points were determined on a

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

• -diol on one of the alkenes would in principle result in the formation of a cyclic ketal. Spiro and cyclic ketals are ubiquitous in pheromones and in marine natural products [51]. The comparatively long effective lifetime of radicals generated under the conditions of the xanthate transfer may be

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• containing lactam, bicyclic, and spiro-bicyclic scaffolds, support was provided for the hypothesis that the bioactive conformation of PLG is a type II β-turn. In addition, studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were

• able to modulate dopamine receptors because of their ability to place the carboxamide NH2 pharmacophore in the same topological space as that seen in the type II β-turn. Extensive studies with the spiro-bicyclic PLG peptidomimetics also established that both positive and negative modes of modulation

• changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of PLG peptidomimetics. Keywords: allosteric modulation; dopamine D2 receptor; peptidomimetic; Pro-Leu-Gly-NH2; spiro-bicyclic scaffold; Review There has been an increasing effort

Synthesis of spiro[dihydropyridine-oxindoles] via three-component reaction of arylamine, isatin and cyclopentane-1,3-dione

• Yan Sun,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 8–14, doi:10.3762/bjoc.9.2

• Yan Sun Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.9.2 Abstract A fast and convenient protocol for the synthesis of novel spiro[dihydropyridine-oxindole] derivatives in satisfactory yields was developed by the three

• scope of this novel reaction is briefly discussed. Keywords: arylamine; cyclopentanedione; isatin; multicomponent reaction; spiro compound; Introduction The spirooxindole is among the most important class of naturally occurring substances, characterized by highly pronounced biological properties, and

• ][13][14]. Considering the above reports, and as part of our program aimed at developing new multicomponent reactions for the construction of complex heterocyclic compounds, we wish in this work to report the efficient synthesis of unprecedented cyclopentyl-fused spiro[dihydropyridine-oxindoles] by the

Features of the behavior of 4-amino-5-carboxamido-1,2,3-triazole in multicomponent heterocyclizations with carbonyl compounds

• Eugene S. Gladkov,
• Katerina A. Gura,
• Svetlana M. Sirko,
• Sergey M. Desenko,
• Ulrich Groth and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2012, 8, 2100–2105, doi:10.3762/bjoc.8.236

• contain cross-peaks between pyrimidine NH and spiro-carbon, which is also in good correlation with structure 4. Analogous elucidations allowed the structures of compounds 7 and 9 to be established. Conclusion In summary, two types of heterocyclization reactions involving 4-amino-5-carboxamido-1,2,3

• '-cyclopentane}-3-carboxamide (4a) or 5,6,7,8-tetrahydro-4H-spiro{[1,2,3]triazolo[5,1-b]quinazoline-9,1'-cyclohexane}-3-carboxamide (4b) under all the conditions tested. The best results were observed in the case of microwave-assisted synthesis in methanol at 120 °C. Spirocompound 4c may be obtained by a

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

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

Palladium-catalyzed dual C–H or N–H functionalization of unfunctionalized indole derivatives with alkenes and arenes

• Gianluigi Broggini,
• Egle M. Beccalli,
• Andrea Fasana and
• Silvia Gazzola

Beilstein J. Org. Chem. 2012, 8, 1730–1746, doi:10.3762/bjoc.8.198

• spiro-products 17 and 18 (Scheme 13). The sole formation of the annulated indole 18 as a single diastereoisomer suggests a mechanism that is strictly closer to the classical oxidative Heck reaction (pathway B) rather than to a Wacker-type reaction (pathway A). In fact, the formation of the product 18 is

• into the esters 50 by hydrolysis. The same reactivity was satisfactorily tested also on the 3-indolylallylcarboxamides 51, giving, however, compounds 49 and 50 already obtained from the substrates 48 (Scheme 29). The formation of 49 and 50 may be reasonably justified by the intervention of the spiro

• /esterification process through iminium intermediates. Cyclization of 3-indolylallylcarboxamides involving 1,2-migration of the acyl group from spiro-intermediates. Domino reactions of 2-indolylallylcarboxamides involving N–H functionalization. Cyclization/acyloxylation reaction of 3-alkenylindoles. Doubly

On the proposed structures and stereocontrolled synthesis of the cephalosporolides

• Sami F. Tlais and
• Gregory B. Dudley

Beilstein J. Org. Chem. 2012, 8, 1287–1292, doi:10.3762/bjoc.8.146

• report focuses on 5,5-spiroketal lactones of the cephalosporolide and related families (Figure 2) [26][27]. Cephalosporolides E and F are co-isolated as a mixture, and previous syntheses likewise produce these compounds as a mixture in the absence of methods to control the spiro-center [28][29][30

• structures of cephalosporolide E and F. Results and Discussion We recently reported the stereocontrolled synthesis of cephalosporolide H (reported structure) and its spiroketal isomer [32]. Our strategy featured the use of zinc salts to control the spiro-center using either steric biases or chelation

• cephalosporolide E for the first time in a stereocontrolled manner. Pheromone spiroketals. Reported structures of the cephalosporolides and penisporolides. Reported and synthesized cephalosporolide H isomers. Stereocontrol of oxygenated 5,5-spiroketals. Synthesis of the reported cephalosporolide H and its spiro

Expanding the chemical diversity of spirooxindoles via alkylative pyridine dearomatization

• Chunhui Dai,
• Bo Liang and
• Corey R. J. Stephenson

Beilstein J. Org. Chem. 2012, 8, 986–993, doi:10.3762/bjoc.8.111

• development [9][10][11]. To our knowledge, most studies of these types of molecules focus on spirooxindoles bearing a pyrrolidine ring at the 3-position of the oxindole core, while few reports expand to formulate the syntheses of other spiro rings. As part of our ongoing reaction-screening objective [12][13

• , spiro [1,3]oxazino compounds having a diene moiety within their molecular framework are susceptible to Diels–Alder (D–A) reactions [22]. Scheme 2 highlights three examples in which compound 3a was exposed to N-substituted maleimides in toluene at 150 °C under microwave irradiation for 0.5 h, and D–A

• structure of compound 3d. X-ray crystal structure of compound 8a. Unexpected alkylative pyridine dearomatization during our previous work on the synthesis of spirooxindole pyranochromenediones. Application of spiro [1,3]oxazino compound 3a in D–A reactions. Reaction of isatins 4 and 1,3-dicarbonyl compounds

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

• centre is the key point of interest, as we believe that, with the judicious selection of appendages, it should allow us to access a range of bicyclic structures, including examples of fused, bridged and spiro bicycles. Preliminary studies into the utility of these substrates in a DOS context have yielded

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

• but with the intention of targeting a piperidin-2-one ring-containing polycyclic scaffold, cyclic imine 5a was added at the second stage. Tetracyclic spiro-lactam 2a was isolated in high enantiomeric purity (90% ee) in good chemical yield (62%, Scheme 8) [111][112]. For the products of the nitro

Synthetic approaches to multifunctional indenes

• Neus Mesquida,
• Sara López-Pérez,
• Immaculada Dinarès and
• Ermitas Alcalde

Beilstein J. Org. Chem. 2011, 7, 1739–1744, doi:10.3762/bjoc.7.204

• in which the (3-indenyl)acetic acid 7 was reduced to the corresponding alcohol 10 and transformed to tosylate 11. However, an attempt to convert the (3-indenyl)ethylsulfonate 11 into the advanced inden-5-amine 9 was ineffective, resulting in the formation of the spiro indene 12 instead, and hence

Access to pyrrolo-pyridines by gold-catalyzed hydroarylation of pyrroles tethered to terminal alkynes

• Elena Borsini,
• Gianluigi Broggini,
• Andrea Fasana,
• Chiara Baldassarri,
• Angelo M. Manzo and
• Alcide D. Perboni

Beilstein J. Org. Chem. 2011, 7, 1468–1474, doi:10.3762/bjoc.7.170

• terminal alkynes with pyrroles is shown in Scheme 2. It is highly probable that the products arise from the vinyl gold species B and F, in turn generated from alkynes 4 after coordination to AuCl3. The formation of F can result by a migration of the acyl group from the spiro center of the transient

• cationic spiro gold complex D, in turn generated by the attack of the more nucleophilic C-2 of the pyrrole nucleus on the intermediate A. On the other hand, complex B can arise from the direct attack of the pyrrolic C-3 on the activated species A or from the migration of the alkyl group on the spiro

Gold(I)-catalyzed synthesis of γ-vinylbutyrolactones by intramolecular oxaallylic alkylation with alcohols

• Michel Chiarucci,
• Mirko Locritani,
• Gianpiero Cera and
• Marco Bandini

Beilstein J. Org. Chem. 2011, 7, 1198–1204, doi:10.3762/bjoc.7.139

• be adaptable allowing a double lactonization event with 1j, hence providing spiro-lactone 2j in 93% yield. Apart from the generality on malonyl substrates, we decided to explore the applicability of the present methodology to less reactive monoester analogs [47]. In this context, readily available

Synthetic applications of gold-catalyzed ring expansions

• David Garayalde and
• Cristina Nevado

Beilstein J. Org. Chem. 2011, 7, 767–780, doi:10.3762/bjoc.7.87

• formation of the 1,4-furan dipole (Scheme 21). In fact, a resonance structure of 60 can be envisaged entailing a gold–carbene and a carbonyl ylide 63. Upon 1,3-dipolar cycloaddition with the alkoxy vinyl ether, bridged bicycle 64 is formed. 1,2-Alkyl migration and bridge opening produces a spiro cation 66

When cyclopropenes meet gold catalysts

• Frédéric Miege,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2011, 7, 717–734, doi:10.3762/bjoc.7.82

• obtained (9m/9’m > 99:1) (33%) when the reaction was carried out at 10 °C (Scheme 5) [18][19]. The reaction was successfully extended to a variety of 3,3-disubstituted cyclopropenes (3-methyl-3-benzylcyclopropene, spiro[2.5]oct-1-ene, 3-benzyl-3-isopropylcyclopropene, 3-tert-butyl-3-methylcyclopropene) and

Metathesis access to monocyclic iminocyclitol-based therapeutic agents

• Ileana Dragutan,
• Valerian Dragutan,
• Carmen Mitan,
• Hermanus C.M. Vosloo,
• Lionel Delaude and
• Albert Demonceau

Beilstein J. Org. Chem. 2011, 7, 699–716, doi:10.3762/bjoc.7.81

• produce the (+)-DMDP (49) and (−)-bulgecinine (50) (Scheme 8). The starting point in the synthesis of (+)-broussonetine G, 53, was the same annulated oxazolone 48 which, after conversion into the Weinreb amide 51, was coupled with the alkyl bromide substituted spiro compound 52 (Scheme 9). In fact, the

Gold-catalyzed heterocyclizations in alkynyl- and allenyl-β-lactams

• Benito Alcaide and
• Pedro Almendros

Beilstein J. Org. Chem. 2011, 7, 622–630, doi:10.3762/bjoc.7.73

• oxycyclization/hydroxylation of 2-azetidinone-tethered alkynols for the synthesis of non-fused, spiro, and fused oxabicyclic β-lactams has been reported [65]. Attempts at a cyclization reaction of terminal alkynols using gold catalysts failed. However, under the appropriate reaction conditions was found that

• order to determine whether the conclusions drawn from the homopropargylic alcohols 22 could be extrapolated to other alkynols, tertiary carbinols 24 were examined. Under similar gold-catalyzed conditions, spiro β-lactams 25 were obtained as single isomers in good yields (Scheme 13). To further probe the

• -azetidinone-tethered homopropargylic alcohols. Gold-catalyzed formation of spiro tetrahydrofuryl-β-lactam hemiacetals from 2-azetidinone-tethered homopropargylic alcohols. Gold-catalyzed formation of fused tetrahydrofuryl-β-lactam hemiacetals from 2-azetidinone-tethered bis- and tris-homopropargylic alcohols

The arene–alkene photocycloaddition

• Ursula Streit and
• Christian G. Bochet

Beilstein J. Org. Chem. 2011, 7, 525–542, doi:10.3762/bjoc.7.61

• the core of Lancifodilactone F [70]. This triterpenoid contains three fused and one spiro cycle and is a very challenging target. Initial attempts to construct the fused seven-, six- and five-membered core were unsuccessful. Introduction of a trimethylsiloxy group on the tether and an oxygen

• mechanism involves the reaction of the olefin with the ipso position of the aromatic ring affording a spiro biradical intermediate. Recombination of these radicals proceeds further until formation of the final compound. Some years later, Kohmoto showed that similar enamides linked to a naphthyl moiety

• completely new reaction Sakamoto has proposed a mechanism involving a ζ-hydrogen abstraction to form a biradical intermediate (Scheme 35, E). The resulting biradical cyclizes to form the spiro compound F upon recombination of the biradical. Re-aromatization affords the carboxylate G, which further attacks

Rh(I)-catalyzed intramolecular [2 + 2 + 1] cycloaddition of allenenes: Construction of bicyclo[4.3.0]nonenones with an angular methyl group and tricyclo[6.4.0.0^1,5]dodecenone

• Fuyuhiko Inagaki,
• Naoya Itoh,
• Yujiro Hayashi,
• Yumi Matsui and
• Chisato Mukai

Beilstein J. Org. Chem. 2011, 7, 404–409, doi:10.3762/bjoc.7.52

• -en-6-one 11, instead the spiro[4.5]deca-1,6-diene derivative 12 was formed exclusively in 87% yield (Table 3, entry 1). After screening several reaction conditions, the tricyclic derivative 11 was obtained in 73% yield along with 12 (24%) when the reaction was carried out in the absence of AgBF4

• under a CO atmosphere (Table 3, entry 2). The [RhCl(CO)dppp]2-catalyzed reaction of 10 under a N2 atmosphere with or without AgBF4 produced the spiro product 12 in 93% and 91% yield, respectively, whereas no spiro product 12 was obtained under thermal conditions without a Rh(I)-catalyst (Table 3

• spiro[4.5]deca-1,6-diene system via β-elimination and subsequent reductive elimination [31][32]. In summary, we have developed the intramolecular Rh(I)-catalyzed PKTR between 1,1-disubstituted allene and 1,1-disubstituted alkene functionalities, which leads to the facile formation of bicyclo[4.3.0