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

• Hong Gao Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.9.330 Abstract The four-component reaction of 2-aminobenzothiazole, aromatic aldehydes, acetylenedicarboxylate and piperidine or pyrrolidine in ethanol afforded the

• spiro compounds by using the in situ generated Huisgen 1,4-dipoles [17][18][19][20][21][22][23][24]. During these research works, we noticed that even through the cyclic secondary amines such as pyrrolidine, piperidine and morpholine also reacted with electron-deficient alkynes to give the Huisgen 1,4

• reaction, we explored the scope of this promising reaction by varying the structure of the secondary cyclic amines. When excess pyrrolidine was used in the reaction by using the above reaction procedure, it was surprising to find that only very low yields of 3-(pyrrolidin-1-yl)-2-pyrrolidinones were

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• triazolium salts 5 and 6 [18][22]. The route to target 7 began by treating N-Boc-trans-4-hydroxy-L-proline methyl ester (11) with diethylaminosulfur trifluoride (DAST) in CH2Cl2 to install the first fluoro substituent (12) with clean configurational inversion (88%, Scheme 1). Oxidation of the pyrrolidine to

• were prepared by an analogous reaction sequence (Scheme 3). Commercially available (S)-(+)-(trifluoromethyl)pyrrolidine 20 was protected (21, quantitative), oxidised to the corresponding lactam (22, 38% over 2 steps) and processed to the target triazolium salt 9 (46%, 3 steps). The non-fluorinated

• triazolium salts 5, 6 and 7 were then compared to examine the conformation of the β-fluoroamine motifs that were the major motivation for this study (Figure 3) [42]. In previous analyses of (S)-2-(fluorodiphenylmethyl)pyrrolidine derivatives, the synclinal-endo conformation was almost exclusively observed in

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• [21]. For example, O’Hagan and co-workers investigated the pyrrolidine-containing molecules 9 and 10 (Figure 3) as ligands of G-quadruplex DNA [22]. The non-fluorinated ligand 9 had some conformational disorder because the pyrrolidine rings were able to interconvert between exo and endo puckers. In

• contrast, the pyrrolidine rings of fluorinated ligand 10 were more rigid, with the fluorine atoms preferring to occupy an axial position consistent with a favourable C–F…N+ interaction (worth approximately 5.0 kcal/mol). This led to a number of changes to the DNA binding mode of 10, including a rotation of

• the entire pyrrolidine ring by 180° relative to that of 9, and several different H-bonding contacts with the DNA as a result. In contrast with the strong charge–dipole effect evident in pyrrolidine 10 (Figure 3), another more subtle interaction is observed in neutral fluorinated pyrrolidines. For

Synthetic scope and DFT analysis of the chiral binap–gold(I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

• María Martín-Rodríguez,
• Luis M. Castelló,
• Carmen Nájera,
• José M. Sansano,
• Olatz Larrañaga,
• Abel de Cózar and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2013, 9, 2422–2433, doi:10.3762/bjoc.9.280

• submitted to different transformations. For example, it could be reduced to the corresponding pyrrolidines employing sodium cyanoborohydride in acidic media. In this reaction, a 1:1 mixture of 2,5-cis-pyrrolidine 13 and its 5-epimer 14 (2,5-trans) was isolated in good chemical yield (71%) (Scheme 7

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• product. On the basis of the abovementioned analysis, a retrosynthetic analysis of (8S,8aS)-5 is displayed in Scheme 5, which features the formation of the fused pyrrolidine ring from the but-3-ene-1-yl group, the expected trans-diastereoselective methylation as the key step, and protected (R)-3

Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of hedgehog signaling

• Johann Moschner,
• Anna Chentsova,
• Nicole Eilert,
• Irene Rovardi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2013, 9, 2328–2335, doi:10.3762/bjoc.9.267

• steps) gave sulfonylamide 21. Reduction of the ester in 21 to the primary alcohol (DIBAl-H, THF, −78 °C to −40 °C, 97%) and cyclization by employing Mitsunobu conditions (n-Bu3P, DEAD, toluene, 0 °C→25 °C, 81%) yielded pyrrolidine 22. Previously devised conditions for the deprotection (1. DDQ, DCE/pH 7

• and 9 it becomes evident that the F-ring is necessary for bioactivity. The piperidine moiety provides a rather rigidly placed nitrogen atom. Nevertheless, a pyrrolidine as in compound 23 still provides the correct orientation of the nitrogen atom. Despite compounds 8 and 9 being inactive in the assay

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

• specifically cleaves at proline residues, it is unsurprising that the members of this drug class exhibit an embedded pyrrolidine ring (or mimic) and additional decoration (a nitrile or fluorinated alkyl substituent is present in order to reach into a local lipophilic pocket). One specific structural liability

Synthesis of axially chiral gold complexes and their applications in asymmetric catalyses

• Yin-wei Sun,
• Qin Xu and
• Min Shi

Beilstein J. Org. Chem. 2013, 9, 2224–2232, doi:10.3762/bjoc.9.261

• afforded pyrrolidine derivative 25 in 46% yield and 17% ee. While using AgSbF6 or AgNTf2 as additives, only trace amounts of 25 were formed. Further screening of silver salts revealed that AgOTs showed the best catalytic activity in this reaction, giving 25 in 72% yield and 27% ee (Table 1, entries 1–6

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

• natural products containing a 1,2,4-oxadiazole ring in their structure (quisqualic acid and phidianidines A and B), the natural product analogs 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) and 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)-1H-pyrrole-2,5-dione (7) were

• compounds 4 and 5 were also confirmed by X-ray structure analysis (Figure 7, Figure 8 and Figure 9). In compound 4 the oxazoline and phenyl rings are approximately coplanar (6°), but the pyrrolidine ring is rotated by 52° with respect to the phenyl ring. The main packing interaction is an offset stacking

• ), 612 (m) cm−1. Synthesis of 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) 0.3 g (0.94 mmol) of 4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobutanoic acid (3) was mixed with an equimolar amount of sodium acetate (0.077 g, 0.94 mmol) in 15 mL of acetic anhydride

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• -dipolar cycloaddition. Carrying out the reaction at 180 °C in tetrahydrofuran provided a separable mixture of pyrrolidine isomers 241 and 242 (1:3.6). The undesired cycloadduct 242 could be equilibrated to 241 due to the reversibility of the reaction. Conversion to the β,γ-cyclohexenone 243 was

• accomplished within 6 consecutive steps. Generation of the dienamine 244 with pyrrolidine in methanol at 60 °C triggered an intramolecular Diels–Alder reaction to provide the full carbon skeleton 245. The final transformations of the synthesis involved a Wittig olefination of the ketone and a

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• for the outcome of the reaction and proline was more effective than pyrrolidine. Additionally, to maximize the yields, the optimal rates for the two catalytic processes need to be similar. Since formation of the iminium ions is much faster than the addition of the enamine nucleophiles, higher yields

• pyrrolidines 43 and 47 (Scheme 12). Xiao also showed that the pyrrolidine ring of 43 could be further oxidized to a fused pyrrole 44 under the same photoredox conditions or by treatment with NBS. Both Ru(bpy)3Cl2 and Ir(bpy)(ppy)2 were found to be effective catalysts. A plausible mechanism for the 1,3-dipolar

• loss of a proton. 1,3-Dipolar cycloaddition of 50 with a dipolarophile 46 furnishes fused pyrrolidine 51 that is further oxidized to pyrrole 52. The Zhu group discovered that the use of α-ketoester 53 as a pronucleophile to intercept the iminium ion of 13 triggered a new cascade reaction en route to

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

• (Scheme 1). In the course of our investigations, we observed that pyrrolidine 4 could be converted into the corresponding pyrrole 5 by a simple isomerization, avoiding the use of oxidants. We describe herein the details of these observations and the scope of this methodology for the concise preparation of

• substituted 2-heteroaromatic decorated N-arylpyrroles. Results and Discussion We first observed the unexpected formation of pyrrole 5a in 50% yield after treatment of pyrrolidine 4a with KCN in DMF (Scheme 2, conditions a). Although obtained in modest yield, we found the original and unique structure of the

• stronger nucleophilic base such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) was tested [25]. Pleasingly, when pyrrolidine 4a was exposed to DBU in CH2Cl2, 5a was obtained in excellent yield (98%, 1 h, conditions b; Scheme 2). The reaction can also be promoted by a catalytic amount of DBU (0.2 equiv

A³-Coupling catalyzed by robust Au nanoparticles covalently bonded to HS-functionalized cellulose nanocrystalline films

• Jian-Lin Huang,
• Derek G. Gray and
• Chao-Jun Li

Beilstein J. Org. Chem. 2013, 9, 1388–1396, doi:10.3762/bjoc.9.155

• yields (Table 2, entries 1–8). However, long chain aldehydes had a lower activity, giving lower yields (Table 1, entries 9, 10). We also observed good to moderate yields when the cyclic dialkylamines such as pyrrolidine, morpholine and azepane were used (Table 2, entries 11–19). Catalyst recycling In

Selective copper(II) acetate and potassium iodide catalyzed oxidation of aminals to dihydroquinazoline and quinazolinone alkaloids

• Matthew T. Richers,
• Chenfei Zhao and
• Daniel Seidel

Beilstein J. Org. Chem. 2013, 9, 1194–1201, doi:10.3762/bjoc.9.135

• resulted in a lower yield than the corresponding pyrrolidine and azepane products (2 and 12, respectively). While differences in conformation may in part account for the observed differences in reactivity (X-ray crystal structures of aminals containing pyrrolidine and piperidine revealed that the

• pyrrolidine-containing aminal adopts a bent structure, whereas the piperidine aminal appears relatively strain-free [34]), this finding likely relates to the reduced propensity of six-membered rings to engage in reactions that form exocyclic double bonds. The isolation of azepinoquinazoline 12 in 73% yield

Study on the total synthesis of velbanamine: Chemoselective dioxygenation of alkenes with PIFA via a stop-and-flow strategy

• Huili Liu,
• Kuan Zheng,
• Xiang Lu,
• Xiaoxia Wang and
• Ran Hong

Beilstein J. Org. Chem. 2013, 9, 983–990, doi:10.3762/bjoc.9.113

• Recently, Tellitu, Dominguez, and co-workers reported an intramolecular oxyamidation of alkene 11 with phenyliodine(III)-bis(trifluoroacetate) (PIFA) (Scheme 3) [46]. The lactam 12 was originally assigned as an unstable intermediate, which should be subsequently reduced to pyrrolidine 13. It was

• particularly striking to us that the arene unprecedentedly stabilizes the primary carbon cation through a neighboring participation in the mechanism proposed by Tellitu et al. To resolve the confusion, we synthesized the corresponding pyrrolidine through an alternative approach (Scheme 4). The amination of

Synthesis of meso-substituted dihydro-1,3-oxazinoporphyrins

• Satyasheel Sharma and
• Mahendra Nath

Beilstein J. Org. Chem. 2013, 9, 496–502, doi:10.3762/bjoc.9.53

• [25], pyrrolidinone [26], pyrrolidine [27] and piperazine [28], to the porphyrin periphery. In addition, many porphyrin dimers and trimers have displayed significant biological efficacy [29] and some of these are used as photosensitizers in PDT applications for the treatment of various types of

A peptidic hydrogel that may behave as a “Trojan Horse”

• Nicola Castellucci,
• Giorgio Sartor,
• Natalia Calonghi,
• Carola Parolin,
• Giuseppe Falini and
• Claudia Tomasini

Beilstein J. Org. Chem. 2013, 9, 417–424, doi:10.3762/bjoc.9.44

• C73H90N10O18S2: C, 60.07; H, 6.21; N, 9.60; found: C, 60.03; H, 6.19; N, 9.57. Dansylamide (C) may be purchased by Sigma-Aldrich. Dansylpyrrolidine (D): A solution of dansyl chloride (1.11 mmol, 0.3 g) and pyrrolidine (0.55 mmol, 0.5 mL) in dry dichloromethane (20 mL) was stirred under a nitrogen atmosphere for

One-pot tandem cyclization of enantiopure asymmetric cis-2,5-disubstituted pyrrolidines: Facile access to chiral 10-heteroazatriquinanes

• Ping-An Wang,
• Sheng-Yong Zhang and
• Henri B. Kagan

Beilstein J. Org. Chem. 2013, 9, 265–269, doi:10.3762/bjoc.9.32

• configurations of these new chiral 10-heteroazatriquinanes are confirmed by X-ray single-crystal diffraction analysis. Keywords: cis-2,5-disubstituted pyrrolidine; 10-heteroazatriquinane; tandem cyclization; X-ray single-crystal diffraction analysis; Introduction The azatriquinane derivatives are an important

• reduction/cyclization was made possible by the cis-configuration of the starting 2,5-disubstituted pyrrolidine 4a. Following the same procedure, 10-heteroazaquinane 5b was obtained in good yield (87%), and the configurations of 5b were assigned to be S, 3R, 6S, 9R (chiral B atom) and 10S (chiral N atom

• pyrrolidine 6b and NH4BF4 in HC(OCH3)3 is heated to 80 °C for 2 h, the light yellow crystals were obtained in good yield after workup (Scheme 3). The same result was obtained by heating the mixture of 6b, NH4BF4 and HC(OCH3)3 in anhydrous toluene under reflux. To our delight, a single crystal was grown from

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• to synthesize 4 from 6, which would lead to the shortest possible synthesis of 1. Nitrile 6 was treated with N-(3-aminopropyl)pyrrolidine (8) to produce aniline 12 in 81% yield (Scheme 1) [19]. This compound was reduced to aniline 13 in 79% yield and converted to the benzimidizole 14 in 63% yield

• available 7 was converted to methyl ester 15 in 90% yield, due to its ease of handling (Scheme 2) [20]. Next, SNAr displacement of the fluoride of 15 by N-(3-aminopropyl)pyrrolidine (8) proceeded in high yield, 99%, to give aniline 16 [20]. Reduction of the nitro group was nearly quantitative and subsequent

Tandem aldehyde–alkyne–amine coupling/cycloisomerization: A new synthesis of coumarins

• Maddi Sridhar Reddy,
• Nuligonda Thirupathi and
• Madala Haribabu

Beilstein J. Org. Chem. 2013, 9, 180–184, doi:10.3762/bjoc.9.21

• , pyrrolidine and salicylaldehydes led to a concomitant cycloisomerization followed by hydrolysis of the resultant vinyl ether to afford coumarins in a cascade process. The reaction proceeded through exclusive 6-endo-dig cyclization and is compatible with halo and keto groups giving coumarins in good to

• )). Similarly, Patil and Raut [24] reported an elegant method for the synthesis of 2-substituted quinolines from 2-aminobenzaldehydes and terminal alkynes by a tandem A3/6-endo-dig-cycloisomerization (Scheme 1, (b)) using a cooperative catalytic system consisting of CuI and pyrrolidine. Prior to these two

• aminoindolizines, 2-(aminomethyl)indoles, imidazopyridines, butenolides and 1,2-dihydroisoquinoline derivatives, respectively, combining these two approaches successfully. Along the same lines, we investigated a reaction between ethoxyacetylene, pyrrolidine and salicylaldehyde in the presence of a transition-metal

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• of the aldol product was observed. Subsequently, Bolm and co-workers also reported an enantio-enrichment of a scalemic aldol product 3b by iterative retro-aldol/aldol reactions of anti-aldol product in the presence of an achiral or racemic catalyst, i.e., pyrrolidine, by magnetically stirring a

• ]. The proposed transition state (TS 1) involves enamine formation between the pyrrolidine unit of the catalyst with the ketone and synergic activation of the aldehyde by hydrogen bonding between carbonyl oxygen and amidic NH of the catalyst. Higher stereoselectivity under solvent-free reaction

• -free ball-milling conditions catalysed by pyrrolidine-derived organocatalysts (Scheme 6) [45]. Both the procedures provided the product in good yield, poor to high diastereoselectivity, and moderate to high enantioselectivity. Two different organocatalysts were identified for aqueous and solvent-free

Design and synthesis of a photoswitchable guanidine catalyst

• Philipp Viehmann and
• Stefan Hecht

Beilstein J. Org. Chem. 2012, 8, 1825–1830, doi:10.3762/bjoc.8.209

• 2E. The therefore necessary urea 4 can be obtained from the addition of pyrrolidine to phenylisocyanate (3). The structure of guanidine 2E was proven by NMR spectroscopy, HRMS, as well as by single-crystal X-ray structure analysis (Figure 1). To our knowledge, this is the first example of an X-ray

Automated three-component synthesis of a library of γ-lactams

• Erik Fenster,
• David Hill,
• Oliver Reiser and
• Jeffrey Aubé

Beilstein J. Org. Chem. 2012, 8, 1804–1813, doi:10.3762/bjoc.8.206

• asymmetric organocatalyzed reaction in the Michael addition step, (b) combining the individual three steps, and (c) automating the process to produce a demonstrative 256 member γ-lactam library. Asymmetric organocatalyzed Michael addition The success of pyrrolidine as the organocatalyst for the Michael

• protocol, we explored the use of various chiral amines in the conjugate addition reaction of propionaldehyde (2{1}) to N-phenylmaleimide (1{1}) (Table 1). Although the achiral pyrrolidine was found to be an efficient catalyst in the reaction [12], this led to a ~1:1 mixture of racemic succinimide

• 4–12%). Although in our previous work aryl acetaldehydes were found to produce decent yields with pyrrolidine [12], similar results were not obtained when the protected diphenylprolinol catalyst I was used. Except for the experiment in Table 3, entry 4, chemical purities >85% were observed for all

Asymmetric desymmetrization of meso-diols by C₂-symmetric chiral 4-pyrrolidinopyridines

• Hartmut Schedel,
• Keizo Kan,
• Yoshihiro Ueda,
• Kenji Mishiro,
• Keisuke Yoshida,
• Takumi Furuta and
• Takeo Kawabata

Beilstein J. Org. Chem. 2012, 8, 1778–1787, doi:10.3762/bjoc.8.203

• pyrrolidine ring such as 3 were prepared from trans-4-hydroxy-L-proline. These catalysts were found to be moderately effective for the asymmetric desymmetrization of meso-diols [11]. C2-Symmetric PPY-catalyst 4 was found to be effective for the chemo- and regioselective acylation of carbohydrates [12][14][16

• ][29][30][31][32][33][34][35][36][37][38]. We have reported the asymmetric desymmetrization of meso-1,2-cyclohexanediol (5) by catalytic enantioselective acylation with catalyst 3 (Scheme 1) [11]. Among various chiral PPY catalysts with dual functional side chains at C(2) and C(4) of the pyrrolidine

• clearly indicates that the (1S,2R)-isomer reacts faster than the (1R,2S)-isomer in the acylation catalyzed by 12b. The results in Table 1 suggest that the amide carbonyl groups at C(2) and C(5) of the pyrrolidine ring of the catalysts 8–14 would play the key role in asymmetric acylation. This is due to

Organocatalytic cascade aza-Michael/hemiacetal reaction between disubstituted hydrazines and α,β-unsaturated aldehydes: Highly diastereo- and enantioselective synthesis of pyrazolidine derivatives

• Zhi-Cong Geng,
• Jian Chen,
• Ning Li,
• Xiao-Fei Huang,
• Yong Zhang,
• Ya-Wen Zhang and
• Xing-Wang Wang

Beilstein J. Org. Chem. 2012, 8, 1710–1720, doi:10.3762/bjoc.8.195

• /hemiacetal sequence with chiral or achiral secondary amines as organocatalysts. Thus, a series of achiral pyrazolidine derivatives were obtained with good yields (up to 90%) and high diastereoselectivities (>20:1) with pyrrolidine as an organocatalyst, and enantioenriched pyrazolidines are also achieved with

• investigated in the presence of several common secondary amines 1a–f as organocatalysts in chloroform. Pyrrolidine (1c) turned out to be an effective catalyst and di-tert-butyl hydrazine-1,2-dicarboxylate (2c) was a potent donor (see Table S1 in the Supporting Information File 1). When di-tert-butyl hydrazine

• -1,2-dicarboxylate (2c) was used as the donor and 20 mol % pyrrolidine (1c) as the catalyst, 5-hydroxypyrazolidine 4a could be obtained in 68% yield with over 20:1 dr after five days (Table 1, entry 1). Thus, the tandem aza-Michael/hemiacetal reaction between di-tert-butyl hydrazine-1,2-dicarboxylate