Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• coupling reactions as well as nucleophilic substitutions have been performed successfully in order to increase the molecular diversity. Keywords: aerobic oxidative coupling; imidazo[1,2-a]-N-heterocycles; gem-difluoroalkyl derivatives; propargylic fluorides; Introduction Nitrogen-containing heterocyclic

• as an attractive precursor to increase the molecular diversity around this scaffold. In order to explore this possibility, we performed two Suzuki–Miyaura reactions, as representative examples of Pd-catalyzed coupling processes (Table 3). They gave the target molecules 8 and 9 in 46% and 53% yields

Synthesis of structurally diverse 3,4-dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions

• Andreas C. Boukis,
• Baptiste Monney and
• Michael A. R. Meier

Beilstein J. Org. Chem. 2017, 13, 54–62, doi:10.3762/bjoc.13.7

• reactions, a large number of structurally diverse compounds could be synthesized. In addition, a one-pot Biginelli–Passerini tandem reaction was demonstrated. All products were carefully characterized via 1D and 2D NMR as well as IR and HRMS. Keywords: Biginelli reaction; molecular diversity

Further exploration of the heterocyclic diversity accessible from the allylation chemistry of indigo

• Alireza Shakoori,
• John B. Bremner,
• Mohammed K. Abdel-Hamid,
• Anthony C. Willis,
• Rachada Haritakun and
• Paul A. Keller

Beilstein J. Org. Chem. 2015, 11, 481–492, doi:10.3762/bjoc.11.54

• ; nitrogen heterocycles; rearrangement; Introduction One of the foci of current organic synthesis is the exploration of new chemical space, with an emphasis on significant heterocyclic molecular diversity [1][2]. Direct applications of such advances in medicinal chemistry, chemical biology and nanochemistry

Concise total synthesis of two marine natural nucleosides: trachycladines A and B

• Haixin Ding,
• Wei Li,
• Zhizhong Ruan,
• Ruchun Yang,
• Zhijie Mao,
• Qiang Xiao and
• Jun Wu

Beilstein J. Org. Chem. 2014, 10, 1681–1685, doi:10.3762/bjoc.10.176

• with 40% yield. To further improve the yield and add to the molecular diversity, N6-benzoyladenine 17 was used as a base to give nucleoside 14 in 87% yield (Scheme 2). All benzoyl protecting groups were removed simultaneously by using ammonia saturated methanol in a sealed press tube to give 15 in 96

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• reduction of both the yield and the reaction rate. The application of sonication to shorten the reaction times was also useful, since compound 4 was obtained after 6 hours with the same dr, although in a lower yield (Table 1, entry 14). To exploit the potential of the Ugi reaction to introduce molecular

• diversity by a one-pot operation, we attempted to realize a four-component (4CR) version. An equimolar mixture of isatin and (S)-phenyl ethylamine was reacted with 2a (2 equiv) and 3a (2 equiv) in methanol in the presence of MgSO4 as a dehydrating agent to promote the formation of the ketimine

Secondary amine-initiated three-component synthesis of 3,4-dihydropyrimidinones and thiones involving alkynes, aldehydes and thiourea/urea

• Jie-Ping Wan,
• Yunfang Lin,
• Kaikai Hu and
• Yunyun Liu

Beilstein J. Org. Chem. 2014, 10, 287–292, doi:10.3762/bjoc.10.25

• of the corresponding β-formylketone/ester substrates or the intolerance of β-formylketones/esters in the Biginelli reaction. In regard to the daily increasing requirements on molecular diversity, developing powerful methods for the rapid synthesis of DHPMs with diverse and unprecedented substitution

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization

• Lisa Moni,
• Luca Banfi,
• Andrea Basso,
• Alice Brambilla and
• Renata Riva

Beilstein J. Org. Chem. 2014, 10, 209–212, doi:10.3762/bjoc.10.16

• Lorenzo Giardini and Sara Piano for preliminary exploratory experiments, Andrea Armirotti and Martina Spallarossa for HRMS, PRIN 2009 ("Synthetic Methodologies for Generation of Biologically Relevant Molecular Diversity") and the University of Genova for funding.

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• ], arylidenerhodanines [25][26], α,β-unsaturated lactones [27], nitrostyrenes [28], acrylic and propiolic esters [29], acrylonitriles [30] and arylidene-1,3-dimethylpyrimidine-2,4,6-triones [31] have been reported. However, the molecular diversity of suitable building blocks for construction of spirooxindoles is by far

Four-component reaction of cyclic amines, 2-aminobenzothiazole, aromatic aldehydes and acetylenedicarboxylate

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

Beilstein J. Org. Chem. 2013, 9, 2934–2939, doi:10.3762/bjoc.9.330

• by deprotonation of basic morpholine. This result also showed that this four-component reaction has an interesting molecular diversity in basic or acidic solution. We also utilized piperidine in this acid-catalyzed four component reaction and obtained the corresponding piperidinium 2-pyrrolidinon-3

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• -selectivity (Table 1, entry 20). Olefination of Garner’s aldehyde Olefination of 1 provides an easy access to chiral 2-aminohomoallylic alcohols A (Scheme 24). The intermediate can be derivatized further, thus providing a route for greater molecular diversity. Diastereoselective dihydroxylation of A with OsO4

Gold(I)-catalyzed hydroarylation reaction of aryl (3-iodoprop-2-yn-1-yl) ethers: synthesis of 3-iodo-2H-chromene derivatives

• Pablo Morán-Poladura,
• Eduardo Rubio and
• José M. González

Beilstein J. Org. Chem. 2013, 9, 2120–2128, doi:10.3762/bjoc.9.249

• of an increase in the molecular diversity, offering a suitable strategy intended for library discovery. It is well known that metal-catalyzed hydroarylation is a powerful reaction to prepare benzofused heterocyclic compounds [29][30][31]. Pt(IV) [32], Pt(II) and Au(I) [33] complexes were early

Creating Complexity

• Donald Craig

Beilstein J. Org. Chem. 2013, 9, 1881–1882, doi:10.3762/bjoc.9.220

• of catalysis, radical chemistry, stereoselective synthesis and molecular diversity. I thank them warmly for their high-quality contributions, which demonstrate the central role of organic synthesis in all its guises, in the creation of complexity. Donald Craig London, July 2013

An organocatalytic route to 2-heteroarylmethylene decorated N-arylpyrroles

• Alexandre Jean,
• Jérôme Blanchet,
• Jacques Rouden,
• Jacques Maddaluno and
• Michaël De Paolis

Beilstein J. Org. Chem. 2013, 9, 1480–1486, doi:10.3762/bjoc.9.168

• regioselective oxidation of these substrates is demonstrated, extending the molecular diversity and versatility of these scaffolds. Keywords: C–H oxidation; isomerization; N-arylpyrrole; organocatalysis; Introduction Due to their presence in some natural products [1] and pharmaceuticals [2][3][4], the

• be expected to follow (Scheme 5). Having established a practical methodology for the preparation of substituted N-arylpyrroles, we next undertook synthetic transformations to extend the molecular diversity of the substrates. While attempts to perform an oxidation of the bis(heteroaryl)methylene

• different anilines and enlarge the molecular diversity of the scaffold. So far the methodology is limited to electron-rich anilines due to the formation and reactivity of the corresponding imines and the stability of the Mannich adduct for the hydroamination step. However, this electronic configuration is

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

• spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] in moderate to good yields. The advantages of this reaction included readily available starting materials, mild reaction conditions, operational simplicity, a widely variety of substrates, and molecular diversity of the products. The

Gold-catalyzed oxycyclization of allenic carbamates: expeditious synthesis of 1,3-oxazin-2-ones

• Benito Alcaide,
• Pedro Almendros,
• M. Teresa Quirós and
• Israel Fernández

Beilstein J. Org. Chem. 2013, 9, 818–826, doi:10.3762/bjoc.9.93

• heterocyclization reactions to afford 1,3-oxazinan-2-ones 3. To increase the molecular diversity by incorporating more 1,3-oxazin-2-ones in the molecule, compound 2g having two allenic carbamate units was used. Notably, bis(allenic carbamate) 2g also undergoes this interesting transformation to give bis(6-methylene

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

• acids [12][13][14] can be selectively directed to the formation of one of the compounds I–III or IV–VI (Figure 1). Such an approach is in good correspondence with the “ideal synthesis” concept [18][19] and allows significant increasing of the molecular diversity of target azoloazine systems. Among the

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

• excellent and the starting materials are accessible by standard methods. The α-alkyl groups are introduced via an enolate alkylation strategy, thus providing variety and the potential for molecular diversity. The key rearrangement steps are generally effected under fairly mild conditions. Experimental

Exploring chemical diversity via a modular reaction pairing strategy

• Joanna K. Loh,
• Sun Young Yoon,
• Thiwanka B. Samarakoon,
• Alan Rolfe,
• Patrick Porubsky,
• Benjamin Neuenswander,
• Gerald H. Lushington and
• Paul R. Hanson

Beilstein J. Org. Chem. 2012, 8, 1293–1302, doi:10.3762/bjoc.8.147

• molecular library was performed to achieve enhanced drug-like and lead-like properties, as well as to assess the molecular diversity. In order to assess diversity, five computational analyses were performed, including Cartesian grid-based chemical diversity analysis [40] Overlay analysis Principal moments

• overlay analysis can be quantified more rigorously via principal moments of inertia (PMI) analysis, which was also employed herein to assess the molecular diversity [42]. PMI analysis utilizes shape-based descriptors: The minimum energy conformation of each library member is determined, PMI ratios are

• drug-like (QED) values and Z-scores While molecular diversity is in itself a topic of intellectual value, in applied sciences it is important to balance this intellectual aspect with suitability toward the intended application. In other words, if one intends to synthesize novel compounds for potential

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

• ]oxazino derivatives from N-substituted isatins and 1,3-dicarbonyl compounds with pyridine derivatives is reported. The reactions provided good to excellent yields. Further exploration of the molecular diversity of these compounds is demonstrated through Diels–Alder reactions. Keywords: chemical diversity

• ; 1,3-dicarbonyl compounds; Diels–Alder reaction; molecular diversity; pyridine dearomatization; spirooxindole; Introduction The spirooxindole is a common structural motif found in a variety of complex alkaloids [1]. Many compounds that possess a spirooxindole moiety exhibit significant biological

• , generated during the reaction, to react with pyridine. Finally, the structure of compound 3d was established by single-crystal X-ray analysis (Figure 2). Further plans to expand the molecular diversity of these compounds utilizing available functionalities are currently underway. As an illustrative example

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

• course and selectivity of the reactions to generate different scaffolds and stereochemistry. This combination of reagent and substrate-based approaches for the generation of molecular diversity can afford many interesting possibilities not achievable by either approach alone. Total synthesis of myrrhine

Synthesis in the glycosciences II

• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2012, 8, 411–412, doi:10.3762/bjoc.8.45

• us go. It is interesting to see that, following this editorial approach, the diversity of titles reflects the diversity of carbohydrate chemistry and biology. There is no other class of natural products with a comparable potential for molecular diversity. There are no other biopolymers so difficult

Efficient oxidation of oleanolic acid derivatives using magnesium bis(monoperoxyphthalate) hexahydrate (MMPP): A convenient 2-step procedure towards 12-oxo-28-carboxylic acid derivatives

• Jorge A. R. Salvador,
• Vânia M. Moreira,
• Rui M. A. Pinto,
• Ana S. Leal and
• José A. Paixão

Beilstein J. Org. Chem. 2012, 8, 164–169, doi:10.3762/bjoc.8.17

• : bismuth(III) triflate; δ-hydroxy-γ-lactones; MMPP; oleanolic acid; triterpenoid; Findings The molecular diversity that arises from research into natural products represents a valuable tool for driving drug discovery and development [1][2]. In this context, pentacyclic triterpenoids are currently regarded

(Pseudo)amide-linked oligosaccharide mimetics: molecular recognition and supramolecular properties

• José L. Jiménez Blanco,
• Fernando Ortega-Caballero,
• Carmen Ortiz Mellet and
• José M. García Fernández

Beilstein J. Org. Chem. 2010, 6, No. 20, doi:10.3762/bjoc.6.20

• centres (α or β), the presence of additional substituents such as sulfate or acyl groups and the overall degree of branching. The molecular diversity of oligosaccharide offers a valuable tool for drug discovery in the areas of biologically important oligosaccharides, glycoconjugates and molecular

• alternating α,α-trehalose motifs and semi-rigid thiourea segments (cyclotrehalans, CTs) [77][78][79][88][89]. Molecular diversity was introduced at the inter-saccharide connectors by exploiting the chemistry of macrocyclic carbodiimides [77][78][79][88][89] as well as by varying the size of the macrocycle

Synthesis of dihydrophenanthridines by a sequence of Ugi-4CR and palladium- catalyzed intramolecular C-H functionalization

• Florence Bonnaterre,
• Michèle Bois-Choussy and
• Jieping Zhu

Beilstein J. Org. Chem. 2008, 4, No. 10, doi:10.3762/bjoc.4.10

• associated with previously known macromolecules. By virtue of their inherent convergence, high productivity, their exploratory and complexity-generating power, multicomponent reactions (MCRs) are undoubtedly well suited for creating molecular diversity. The combination of MCRs with an efficient post