Synthesis of chiral N-phosphinyl α-imino esters and their application in asymmetric synthesis of α-amino esters by reduction

• Yiwen Xiong,
• Haibo Mei,
• Lingmin Wu,
• Jianlin Han,
• Yi Pan and
• Guigen Li

Beilstein J. Org. Chem. 2014, 10, 653–659, doi:10.3762/bjoc.10.57

• Research Institute of Nanjing University, Changzhou, 213164, China Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, 79409-1061, USA 10.3762/bjoc.10.57 Abstract A variety of chiral N-phosphinyl α-imino esters have been synthesized for the first time from ketoesters and

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

• attractiveness in biological and medicinal researches, DHPMs have also been demonstrated as quite flexible precursors for the synthesis of many other derived heterocyclic scaffolds [13]. For a rather long period, the Biginelli reaction involving the condensation of aldehydes, β-ketoesters and ureas (thioureas

• ) [14] has been dominantly employed for DHPMs synthesis in both racemic [15][16][17][18] and asymmetric versions [19][20][21][22][23]. Despite of many recognized advantages of the Biginelli reaction, the product diversity suffered from limitations because β-ketoesters or 1,3-diketones are intrinsically

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

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

Asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with α-fluoro-β-keto esters

• Lin Yan,
• Zhiqiang Han,
• Bo Zhu,
• Caiyun Yang,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2013, 9, 1853–1857, doi:10.3762/bjoc.9.216

• conjugate addition and Mannich reaction of α-fluoro-β-ketoesters with excellent results [38][39][40]. Herein, we wish to report the first allylic alkylation of MBH carbonates with α-fluoro-β-ketoesters in excellent enantioselectivities and moderate diastereoselectivities, furnishing enantiopure fluorinated

• (entry 19). A slight increase in enantio- and diastereoselectivity could be obtained when the reaction temperature was decreased to 10 °C, but the reaction rate became too sluggish to be useful (Table 1, entry 20). Using the established conditions, allylic alkylations of α-fluoro-β-ketoesters 1b–g with

• MBH carbonate 2a were found to afford the products 3ba–ga in 67–79% yield with 88–96% ee and 3:1 to 4:1 dr (Table 2, entries 1–6). The results showed that the introduction of various aryl substituents in α-fluoro-β-ketoesters did not affect the reactivity and stereoselectivity. Subsequently, the scope

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

• Trevor A. Hamlin and
• Nicholas E. Leadbeater

Beilstein J. Org. Chem. 2013, 9, 1843–1852, doi:10.3762/bjoc.9.215

• -ketoesters and aromatic aldehydes to yield dihydropyrimidines has received significant attention, these products having pharmacological activity including calcium channel modulation, mitotic kinesin Eg5 inhibition, and antiviral and antibacterial activity [49][50]. The Biginelli reaction has been performed

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• (3% ee). The usage of Boc for the N-protected group in aziridine resulted in no enantioselectivity under the optimum conditions. The organocatalytic enantioselective ring-opening of N-protected aziridines by β-ketoesters by means of cinchona alkaloid-derived PTCs (Figure 3, OC-12 to OC-19) for

A reductive coupling strategy towards ripostatin A

• Kristin D. Schleicher and
• Timothy F. Jamison

Beilstein J. Org. Chem. 2013, 9, 1533–1550, doi:10.3762/bjoc.9.175

• obtained for either of the individual steps from the methyl series that it replaced. The cleavage of TMSE β-ketoesters with TBAF·3H2O has been described in the literature as a chemoselective method for decarboxylation in the presence of other types of β-ketoesters [64]. Comparable yields for the

• elimination could sometimes be observed; however, this typically occurred in less than 10%. Given these results, it seems that the fluoride-mediated deprotection of TMSE β-ketoesters is deserving of further exploration and utilization as a method for the decarboxylation of sensitive synthetic intermediates

Mechanistic studies on the CAN-mediated intramolecular cyclization of δ-aryl-β-dicarbonyl compounds

• Brian M. Casey,
• Dhandapani V. Sadasivam and
• Robert A. Flowers II

Beilstein J. Org. Chem. 2013, 9, 1472–1479, doi:10.3762/bjoc.9.167

• -electron oxidations employing δ-aryl-β-dicarbonyl compounds have been carried out on arenes containing pendant β-ketoesters [10][11]. When Mn(III)-based oxidants are employed, secondary oxidations of the 2-tetralone products can occur [10][11]. Cerium(IV) ammonium nitrate (CAN) is a versatile, inexpensive

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

• ) under ball-milling (400 rpm) to provide an easy access to Michael adducts 10 in good to high yield (63–95%) and excellent enantioselectivity (91–99% ee). The chiral squaramide IX also catalyses the Michael reaction of β-ketoesters 11 with nitrostyrene to provide Michael adducts 12 in 73–95% yield, 1.4:1

• nitrogen activates and orients the dicarbonyl compounds to provide the Michael adduct in high enantioselectivity. Application of grinding with pestle and mortar for highly stereoselective Michael addition of trisubstituted β-ketoesters to nitroalkene derivatives was reported by Chimni’s group (Scheme 8

• ) [48]. Grinding an equimolar quantity of six/five-membered cyclic β-ketoesters 13 and various nitroalkenes 7, including nitrodienes, in the presence of 5 mol % of cupreine-derived organocatalyst X provided Michael adducts 14 in good to high yield (72–99%) and good to excellent stereoselectivity (85–99

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

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

Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones

• Sergei Žari,
• Tiiu Kailas,
• Marina Kudrjashova,
• Mario Öeren,
• Ivar Järving,
• Toomas Tamm,
• Margus Lopp and
• Tõnis Kanger

Beilstein J. Org. Chem. 2012, 8, 1452–1457, doi:10.3762/bjoc.8.165

• enantioenriched products through a carbon–carbon bond formation [1][2][3][4][5]. Recently, unsaturated 1,4-dicarbonyl compounds, such as 1,4-ketoesters [6][7][8], 1,4-diketones [9], 1,4-ketoamides [9][10] and dialkylfumarates [11], have been the substrates for this reaction. The reaction products can undergo

Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone

• Jin-Sheng Yu,
• Feng Zhou,
• Yun-Lin Liu and
• Jian Zhou

Beilstein J. Org. Chem. 2012, 8, 1360–1365, doi:10.3762/bjoc.8.157

• be a powerful strategy for the α-arylation of β-ketoesters and aldehydes. Inspired by their work, we anticipated that the catalytic asymmetric addition of 3-aryloxindoles to quinones would possibly install a hydroquinone moiety at the C3 position of oxindole to furnish the desired chiral 3,3

Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of β-ketoesters

• Wen-Bin Yi,
• Xin Huang,
• Zijuan Zhang,
• Dian-Rong Zhu,
• Chun Cai and
• Wei Zhang

Beilstein J. Org. Chem. 2012, 8, 1233–1240, doi:10.3762/bjoc.8.138

• , Boston, MA 02125, USA 10.3762/bjoc.8.138 Abstract A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of β-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from

• organofluorine chemistry plays an important role in the life sciences [3][4]. A fluorine atom has been introduced to the α-position of some biologically interesting β-ketoesters, such as erythromycin and sesquiterpenic drimane (Figure 1) [5][6]. The achiral fluorination of β-ketoesters can be achieved by

• imido-protected phenylglycines (up to 94% ee), indanones and tetralones (up to 91% ee), ethyl α-cyanotolyl acetates (up to 87% ee), and cyclic β-ketoesters (up to 80% ee) [15]. A catalytic approach for the cinchona alkaloids and Selectfluor combinations has also been developed [16]. The Togni group

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

• reaction. Keywords: α-aminoacids; carbonyl ylides; cycloaddition; α-diazo-β-ketoesters; sulfonium ylides; Introduction The synthetic potential of diazo compounds, in particular of α-diazoketones and α-diazoesters, is greatly widened by the ability of the derived carbene or metal-carbene intermediates to

• -β-ketoesters 1, stable four- to seven-membered cyclic ylides 2 were obtained (Scheme 1); in the case of R2 = allyl, however, the ylides underwent a spontaneous [2,3]-sigmatropic rearrangement. On the other hand, the conversion of methionine-derived diazoketone 3 into the cyclic sulfonium ylide 4 was

• , yielding either a cyclic sulfonium ylide or a six-ring carbonyl ylide. In fact, it has been found that Rh(II)-catalyzed dediazoniation of α-diazo-β-ketoesters with γ-phthalimido [18][19] or related [20] substituents gives rise to cyclic carbonyl ylides, which were trapped by intermolecular cycloaddition

N-Heterocyclic carbene/Brønsted acid cooperative catalysis as a powerful tool in organic synthesis

• Rob De Vreese and
• Matthias D’hooghe

Beilstein J. Org. Chem. 2012, 8, 398–402, doi:10.3762/bjoc.8.43

• -unsaturated aldehydes [18], the enantioselective synthesis of cyclopentenes from α,β-unsaturated aldehydes and α,β-unsaturated ketones [19], and the preparation of cyclopentanes through the reaction of enals and β,γ-unsaturated α-ketoesters [20]. Discussion Recently, Rovis et al. reported that the acetate

Development of the titanium–TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

• Lukas Hintermann,
• Mauro Perseghini and
• Antonio Togni

Beilstein J. Org. Chem. 2011, 7, 1421–1435, doi:10.3762/bjoc.7.166

• Lewis acids catalyze the α-fluorination of β-ketoesters by electrophilic N–F-fluorinating reagents. Asymmetric catalysis with TADDOLato–titanium(IV) dichloride (TADDOL = α,α,α',α'-tetraaryl-(1,3-dioxolane-4,5-diyl)-dimethanol) Lewis acids produces enantiomerically enriched α-fluorinated β-ketoesters in

• ][32][33] and Shibata [34][35]. Second, the research efforts of our group towards realizing metal-catalyzed fluorinations [36][37][38] and asymmetric catalytic fluorination reactions [39], successfully channeled into the discovery of a catalytic asymmetric α-fluorination of β-ketoesters (Scheme 1) by

• means of the reagent F–TEDA and chiral titanium Lewis acid catalysts of the TiCl2(TADDOLate) type [40][41][42]. The same catalytic reaction principle has also allowed the performance of asymmetric chlorinations and brominations of β-ketoesters [43][44][45]. After the initial report [40], many metal

Oxidative allylic rearrangement of cycloalkenols: Formal total synthesis of enantiomerically pure trisporic acid B

• Silke Dubberke,
• Muhammad Abbas and
• Bernhard Westermann

Beilstein J. Org. Chem. 2011, 7, 421–425, doi:10.3762/bjoc.7.54

• 2455, 11415 Riyadh, Saudi Arabia Martin-Luther-University, Department of Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany 10.3762/bjoc.7.54 Abstract Enantiomerically highly enriched unsaturated β-ketoesters bearing a quaternary stereocenter can be utilized as building blocks for

• synthesis of this stereogenic unit and solutions have been found, e.g., by Christoffers and d’Angelo [9][10][11]. We have already disclosed our results to obtain these products highly enantiomerically enriched by pig liver esterase (PLE) catalyzed saponification of α-substituted β-ketoesters [12][13]. We

• have now extended this methodology towards the saponification of unsaturated β-ketoesters (±)-1a,b (Scheme 1) to provide a convenient access to highly functionalized cyclohexenones in optically pure form. In addition, we show that non-racemic chiral α-substituted, β-ketoesters such as (−)-1c can be

Approaches towards the synthesis of 5-aminopyrazoles

• Ranjana Aggarwal,
• Vinod Kumar,
• Rajiv Kumar and
• Shiv P. Singh

Beilstein J. Org. Chem. 2011, 7, 179–197, doi:10.3762/bjoc.7.25

• (Scheme 32) [74]. Dodd et al. [75] have reported an efficient solid-support synthesis of 5-N-alkylamino and 5-N-arylaminopyrazoles 123. Heating the β-ketoesters 120 with resin-bound amines 119 in resin-compatible solvents, such as NMP or toluene, in the presence of DMAP gave the corresponding resin

Highly substituted benzannulated cyclooctanol derivatives by samarium diiodide-induced cyclizations

• Jakub Saadi,
• Irene Brüdgam and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2010, 6, 1229–1245, doi:10.3762/bjoc.6.141

• described the efficient synthesis of cyclooctanol and cyclooctenol derivatives by samarium diiodide-induced 8-endo-trig and 8-endo-dig cyclizations of γ-styryl- [20][31][33] and γ-phenylalkynyl-substituted [20][32] ketoesters. Recently, we have also reported our preliminary results on cyclizations of

• an add-on to our previous observations [33], we started our experiments with the cyclization of ketoesters 5a/b containing a cycloheptanone subunit. Here only the unlike-configured [45] 5a furnished the expected benzannulated tricyclic compound 6 in moderate yield (Scheme 3). The like-configured

• ring and their neighbouring protons. The cis-vicinal protons indicated strong correlations, while the trans-vicinal protons, where the dihedral angle was close to 180°, show none or almost no correlations between each other (Figure 2). In cyclizations of the (2-propenyl)phenyl-substituted ketoesters

Systematic investigations on the reduction of 4-aryl-4-oxoesters to 1-aryl-1,4-butanediols with methanolic sodium borohydride

• Subrata Kumar Chaudhuri,
• Manabendra Saha,
• Amit Saha and
• Sanjay Bhar

Beilstein J. Org. Chem. 2010, 6, 748–755, doi:10.3762/bjoc.6.94

• describe herein our systematic investigations to elucidate the different parameters involved in these reactions and to establish their synthetic usefulness. Results and Discussion When, the γ-aryl-γ-ketoesters (1a–1f) were treated with methanolic NaBH4 (4 equiv) at room temperature (room temperature

• implies 30 °C throughout) both the oxo- and the alkoxycarbonyl moieties were reduced to give the diols (2a–2f), as shown in Scheme 1. γ-Aryl-α,β-unsaturated-γ-ketoesters (1g and 1h), on similar treatment, furnished the saturated diols (2a and 2b) by the reduction of both the keto and the ester groups

• ][22][23][24][25][26][27] for the chemoselective reduction of the keto group of all types of γ-oxoesters. Mechanistic rationale for diol formation during the reduction of a γ-aryl-α,β-unsaturated-γ-ketoester with methanolic NaBH4. Facile reduction of γ-aryl-γ-ketoesters to the corresponding diols with

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

• Norio Shibata,
• Andrej Matsnev and
• Dominique Cahard

Beilstein J. Org. Chem. 2010, 6, No. 65, doi:10.3762/bjoc.6.65

• trifluoromethylation of aliphatic alcohols and these are now commercially available. In 2008, we reported a novel fluorinated Johnson-type reagent for electrophilic trifluoromethylation of carbon-centered nucleophiles. This reagent has demonstrated high efficiency in trifluoromethylation of cyclic β-ketoesters and

• ]thiophenium salts have also demonstrated high ability for trifluoromethylation of β-ketoesters and dicyanoalkylidenes to yield the trifluoromethylated products with a quaternary carbon center, even if the substrates have a rather unreactive acyclic system. In this review, we wish to briefly provide a

• conditions to give ortho-trifluoromethylated arenes in good yields (Scheme 7). Togni’s reagent (37, see later in the text) could be used for this reaction, although product yields were as low as 11%. The reaction conditions for trifluoromethylation of silyl enol ethers and β-ketoesters were reinvestigated by

Continuous flow based catch and release protocol for the synthesis of α-ketoesters

• Alessandro Palmieri,
• Steven V. Ley,
• Anastasios Polyzos,
• Mark Ladlow and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2009, 5, No. 23, doi:10.3762/bjoc.5.23

• , Melbourne, Australia, 3169 Uniqsis, Shepreth, Cambridgeshire, SG8 6GB, United Kingdom 10.3762/bjoc.5.23 Abstract Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of α-ketoesters is reported. Keywords: catch

• and release; flow synthesis; α-ketoesters; mesoreactor; polymer supported reagents; Introduction Organic synthesis is changing rapidly owing to the discovery of processes that challenge current dogma and lead to the invention of new chemical reactions [1][2]. Likewise, new synthesis tools are

• chemical syntheses [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. In this work we report the use of the Uniqsis FlowSyn™ continuous flow reactor [55] (Figure 1) to effect a flow-based preparation of α-ketoesters. The key feature of this process is the application of a catch and