Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• -indanone [37]. In this synthesis, a mixture of diethyl 2-(3,5-dimethoxybenzyl)malonate and methanesulfonic acid was stirred at 100 °C for 2 h and 5,7-dimethoxy-1-indanone was obtained in excellent yield (95%). A new route for the synthesis of an anticancer agent, benzopyronaphthoquinone 51 from the

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• intriguing feature of this molecule is the highly oxygenated carbon chain in which eight hydroxy groups, one of which is used for lactone formation, are contiguously aligned. A 1,3-diol is a common structural element in aliphatic polyketides because the incorporation of malonate-precursors gives rise to the

• pathway [22]. In this study, biosynthetic precursors of 1 were investigated for further genetic and enzymatic studies. Results and Discussion It was obvious from its structure that 1 was synthesized through the malonate pathway. First, [1,2-13C2]acetate was fed to the culture to ensure the alignment of

• malonate units. In the 13C NMR spectrum, split signals arising from 13C–13C couplings were observed for six pairs of carbons: C-11/C-12, C-13/C-14, C-15/C-16, C-17/C-18, C-19/C-20, and C-21/C-22 (Table 1, Figure S1 in Supporting Information File 1). In the 2D-INADEQUATE spectrum of 13C-labeled 1 obtained

Diastereoselective anodic hetero- and homo-coupling of menthol-, 8-methylmenthol- and 8-phenylmenthol-2-alkylmalonates

• Matthias C. Letzel,
• Hans J. Schäfer and
• Roland Fröhlich

Beilstein J. Org. Chem. 2017, 13, 33–42, doi:10.3762/bjoc.13.5

• solution in the range of 5–10 °C with a coolant of −25 °C. The further work-up follows the procedure given for the hetero-coupling reaction. General procedure for the preparation of the menthol esters: To a solution of 4.3 mmol of monobenzyl malonate 5 or 6 in 20 mL dry methylene chloride 0.8 mL thionyl

Supramolecular frameworks based on [60]fullerene hexakisadducts

• Andreas Kraft,
• Johannes Stangl,
• Ana-Maria Krause,
• Klaus Müller-Buschbaum and
• Florian Beuerle

Beilstein J. Org. Chem. 2017, 13, 1–9, doi:10.3762/bjoc.13.1

• , Germany 10.3762/bjoc.13.1 Abstract [60]Fullerene hexakisadducts possessing 12 carboxylic acid side chains form crystalline hydrogen-bonding frameworks in the solid state. Depending on the length of the linker between the reactive sites and the malonate units, the distance of the [60]fullerene nodes and

• crystallization of C3 and also synthesized the next homologue C4 starting from malonate 1 [59] according to a standard two-step protocol via a sixfold Bingel reaction followed by acidic deprotection (Scheme 1). As we observed the insertion of MeOH molecules into the hydrogen-bonding network of HFF-1 [57], we also

• are cross-linked by hydrogen bonding. Thereby, six of the twelve side arms form linear COOH dimers (four intralayer and two interlayer) and two carboxylic acids are bound to malonate ester groups from adjacent layers (see Figure S10 in Supporting Information File 1). The remaining four carboxylic acid

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• obtained in quantitative yield as a clean product with no need for purification. We also investigated the continuous-flow reduction of nitro ester 5, which can be conveniently prepared in one step through the organocatalyzed addition of diethyl malonate to trans-β-nitrostyrene promoted by a chiral thiourea

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• ], or malonate diesters via Claisen condensations followed by hydrolysis and decarboxylation. The greenest routes appear in the [4 + 2] strategy. The three-step route beginning with photochemical ring opening of cyclobutenone to give vinylketene, followed by Diels–Alder addition to ethylene leading to

Et₃B-mediated and palladium-catalyzed direct allylation of β-dicarbonyl compounds with Morita–Baylis–Hillman alcohols

• Ahlem Abidi,
• Yosra Oueslati and
• Farhat Rezgui

Beilstein J. Org. Chem. 2016, 12, 2402–2409, doi:10.3762/bjoc.12.234

• further used as synthetic intermediates in numerous synthetic routes to heterocyclic compounds and molecules of biological interest [41][42]. Results and Discussion We first investigated the allylation of diethyl malonate (2a) with the allylic alcohol 1a in DMF in the presence of Pd(OAc)2 (10 mol %), PPh3

• , carried out in DMF at 80 °C, gave a better result (30% yield in 12 h), using, in addition to NaH (0.5 equiv), 1 equiv of Et3B (Table 1, entry 3). Moreover, a remarkable improvement in yield (60% in 6 h) was also observed for the allylation of diethyl malonate (2a) with the MBH alcohol 1a using an excess

• of Et3B (3 equiv) and 1 equiv of NaH (Table 1, entry 4). Mechanistic considerations Scheme 1 illustrates the most probable catalytic cycle for the allylation of diethyl malonate (2a) with allyl alcohol 1a. We assume that there is first an activation of 1a through its conversion into I1 using Et3B [29

Enantioconvergent catalysis

• Justin T. Mohr,
• Jared T. Moore and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2016, 12, 2038–2045, doi:10.3762/bjoc.12.192

• stereoablative approach (Scheme 3) [22][23]. Deprotonation and elimination of the halide in oxindole (±)-8 leads to achiral azaxylylene intermediate 11, which is trapped with malonate nucleophiles to form all-carbon quaternary centers. The overall transformation is unusual since oxindoles are typically

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• ) (rhiPKS) and synthetic SNAC-thioesters revealed that the chain branch originates from a syn-selective Michael addition of an ACP-bound malonate unit 133 to a KS-bound α,β-unsaturated thioester 132 (Scheme 20b) [130]. This results in an intermediate 134 in which the ACP and the KS domain are covalently

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• chiral calcium alkoxide complex was generated in situ by mixing Ca(OEt)2, PyBox ligand (S,S)-88, and phenol 89. The authors found that the slow addition of malonate 86 and the use of phenol 89 and ethanol as additives were all crucial for achieving high yield and enantioselectivity, although the exact

NeoPHOX – a structurally tunable ligand system for asymmetric catalysis

• Jaroslav Padevět,
• Marcus G. Schrems,
• Robin Scheil and
• Andreas Pfaltz

Beilstein J. Org. Chem. 2016, 12, 1185–1195, doi:10.3762/bjoc.12.114

• standard test reaction of (E)-1,3-diphenylallylacetate with dimethyl malonate as nucleophile (Scheme 8). The two catalysts derived from ligand 14 with a free hydroxy group and the corresponding triethylsilyl-protected derivative both performed well affording enantioselectivities of 90% and 98% ee

Separation and identification of indene–C₇₀ bisadduct isomers

• Bolong Zhang,
• Jegadesan Subbiah,
• David J. Jones and
• Wallace W. H. Wong

Beilstein J. Org. Chem. 2016, 12, 903–911, doi:10.3762/bjoc.12.88

• ] and C70 bis-malonate isomers [17], was expected to provide further information on adduct configurations. The UV–vis spectra of fractions 1, 2 and 3 showed very similar spectral features when compared with the spectrum of the 5 o’clock isomer of C70 bis-malonate, suggesting that they are all 5 o’clock

• to the 12 o’clock C70 bis-malonate (Figure 6c). Thus the eight major regioisomers of IC70BA were identified. However, the remaining fractions 5–8, were also confirmed to be IC70BA isomers by mass spectrometry. Since the UV–vis spectrum of these fractions did not correlate to those of the known α

• bisadducts: a) fraction 1, 2, 3 and 5 o`clock bis-malonate [17]; b) fraction 4, 9-1 and 2 o`clock-B of IC70BA [9]; c) fraction 10, 11 and 12 o`clock bis-malonate [17]. Schematic diagram of the architecture of BHJ solar cell devices (a) and J−V curves of the devices containing P3HT and each IC70BA fractions

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• first tested in the reaction of trans-nitrostyrene (1a) with diethyl malonate (2a), leading to the enantioenriched addition product 4aa with a single stereocenter. In order to the creation of two tertiary-quaternary contiguous stereocenters (5aa) we also used ethyl 2-oxocyclopentanecarboxylate (3a) as

• of nucleophile and 10 mol % of catalysts (entries 1–4 and 9–11 in Table 1). As a general trend, the reactions were faster, and much more stereoselective for ketoester 3a than for diethyl malonate 2a, and that the difference was specially remarkable when supported ethylenediamine-derived thioureas II

• next consider the reaction of some 4-substituted nitrostyrenes (1b–d) with diethyl malonate (2a), and the addition of a range of β-functionalized nucleophiles 2b–g to 1a promoted by supported catalysts IV (5 mol %) and V (2 mol %), respectively (Scheme 2 and Table 2). The results obtained in the

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• elongated by a butyrate moiety. Subsequently three further elongation steps, this time using malonate as extender units, follow. This results in the incorporation of acetate units via Claisen-condensation reactions. The reductive domains, i.e., ketoreductase (KR) and dehydration (DH) domains, present in the

• formation for the ajudazols A and B in Chondromyces crocatus Cm c5 [80]. 2.2 Biosynthesis by PKSII systems In the type II PKS-catalyzed biosynthesis, the subunit type of such megaenzyme systems, the starter molecule and the extender units, mostly malonate molecules, are assembled at the same ACP. A

• encoded by a set of genes architecturally similar to most other type II PKS clusters. EncA represents the KSα, EncB the KSβ, and EncC the ACP domain. First, an uncommon benzoate starter unit gets elongated by seven malonate molecules. This nascent carbon chain undergoes a rare Favorskii-like rearrangement

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• ethyl malonate, producing the active nucleophile, while the thiourea group activates the electrophile (Scheme 6). The above catalytic reaction provided products with yields up to 99%, dr up to 93:7 and ee up to 93%. Carter and co-worker utilized a similar primary amine-thiourea, organocatalyst 11, in an

• malonates 65 to 3-nitro-2H-chromenes 66, which provided the substituted chromanes 67 in moderate to excellent yields and good enantioselectivities (Scheme 23) [33]. Catalyst (S,S)-68 is postulated to catalyze the reaction in a bifunctional manner: the tertiary amine deprotonates the malonate and the

• , Xu and co-workers described a three-compound reaction between dialkyl malonate 222, nitro-alkene 82 and substituted enal 154, catalyzed by the chiral quinine-derived thiourea 57 and organocatalyst 223, affording product 224 with a substituted cyclohexane-ring core (Scheme 70) [89]. The experimental

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• -additions that have been facilitated by CPD and CPN derived catalysts. For example, and amongst the earliest examples in the field, underivatized CPD or CPN were used in the addition of dimethyl malonate (40) to a range of nitrostyrenes 41, giving the resulting adducts with excellent enantioselectivity

• . A cupreidine derived catalyst induces a dynamic kinetic asymmetric transformation. Cupreine derivative 38 has been used in an organocatalytic asymmetric Friedel–Crafts reaction. Examples of 6’-OH cinchona alkaloid catalyzed processes include: (a) Deng’s addition of dimethyl malonate into

Spiro-fused carbohydrate oxazoline ligands: Synthesis and application as enantio-discrimination agents in asymmetric allylic alkylation

• Jochen Kraft,
• Martin Golkowski and
• Thomas Ziegler

Beilstein J. Org. Chem. 2016, 12, 166–171, doi:10.3762/bjoc.12.18

• chiral ligands in palladium-catalyzed allylic alkylation of 1,3-diphenylallyl acetate with dimethyl malonate. The D-fructo-PyOx ligand provided mainly the (R)-enantiomer while the D-psico-configurated ligand gave the (S)-enantiomer with a lower enantiomeric excess. Keywords: asymmetric catalysis

• benchmark test for selectivity, the palladium-catalyzed asymmetric addition of dimethyl malonate to 1,3-diphenylallyl acetate was often used in the literature for testing the scope of carbohydrate derived ligands for this purpose [9][10][11][12][13]. For instance, Kunz and Gläser have demonstrated the

• -dipolar cycloaddition of 2,6-pyridinedicarbonitrile N,N-dioxide to acetyl protected exo-glucal. The performance of ligand A in asymmetric catalysis was then tested in the palladium-catalyzed allylic addition of dimethyl malonate to 1,3-diphenylallyl acetate which, however, afforded the desired allylic

New metathesis catalyst bearing chromanyl moieties at the N-heterocyclic carbene ligand

• Agnieszka Hryniewicka,
• Szymon Suchodolski,
• Agnieszka Wojtkielewicz,
• Jacek W. Morzycki and
• Stanisław Witkowski

Beilstein J. Org. Chem. 2015, 11, 2795–2804, doi:10.3762/bjoc.11.300

• -trimethylphenol analogously to the procedure described for 2,2,5,8-tetramethyl-6-chromanol by Dean [27]. 2,3-Dihydroxy-1,4-dioxane was obtain according to Venuti [37]. Substrates for testing catalysts in RCM reactions were prepared by allylation of commercial diethyl malonate with allyl bromide and/or 3-chloro-2

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• [24][25][26]. In this context, our group recently introduced an interesting asymmetric organo-cascade reaction of 2-cyanobenzaldehyde (5) with malonate 6. This resulted in enantioenriched 2-(1-oxoisoindolin-3-yl)malonate 7 which is supposed to serve as a potentially useful building block for further

• with dimethyl malonate at room temperature (Table 1). We first identified the combination of DCM and solid K2CO3 as the best-suited solvent–base system for this reaction, however etheral or aromatic solvents or aqueous (alternative) bases generally gave significantly lower selectivities (this was

• )malonate ((S)-7), according to Scheme 2. We firstly focused on two well-known mild procedures in order to avoid the classical harsh acidic conditions. Disappointingly, modifications of the Krapcho decarboxylation performed with a LiCl/H2O/DMF mixture under reflux [36][37] led to partial racemization of the

Biocatalysis for the application of CO₂ as a chemical feedstock

• Apostolos Alissandratos and
• Christopher J. Easton

Beilstein J. Org. Chem. 2015, 11, 2370–2387, doi:10.3762/bjoc.11.259

• 10 is fed to central metabolism while the other is used in a subsequent cycle. As seen in Scheme 4, acetyl-CoA (10) is carboxylated by a bifunctional acetyl-CoA/propionyl-CoA carboxylase to malonyl-CoA (15) with HCO3− and hydrolysis of ATP. The malonate 15 is reduced to 3-hydroxypropionate (16), in

Olefin metathesis in air

• Lorenzo Piola,
• Fady Nahra and
• Steven P. Nolan

Beilstein J. Org. Chem. 2015, 11, 2038–2056, doi:10.3762/bjoc.11.221

• diallylmalonate (29) (Table 5), 93a, 93b, 93d and 93e were found more active than 85. When diethyl allyl(methallyl)malonate (77) and N,N-bis(methallyl)tosylamide (95) were used, catalysts 93a and 93b performed better than others. A full scope, involving an ene–yne reaction, was carried out with these two

• –d, Scheme 9) [84]; phophite-based complexes were thus synthesized to evaluate possible positive effects of these ligands in alkene metathesis reactions. Their stability at high temperatures allowed their use in the RCM of bis(methallyl)tosylamide (95) and diethyl bis(methallyl)malonate leading to

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

• Ivan Bassanini,
• Karl Hult and
• Sergio Riva

Beilstein J. Org. Chem. 2015, 11, 1583–1595, doi:10.3762/bjoc.11.174

• the alkaline protease from Bacillus subtilis on 7 [25]. The carboxyacetyl (malonyl) derivative of some flavonoid glycosides (i.e., 8b) and of ginsenoside Rg1 (9b) could be obtained with two-step sequences. The preliminary CAL-B catalyzed acylations of 8 with dibenzyl malonate and of 9 with bis(2,2,2

• -trichloroethyl)malonate to give the mixed malonyl derivatives 8a and 9a, respectively, were followed either by a palladium-catalyzed hydrogenolysis of the benzyl moiety to give 8b [26], or by a selective chemical removal of 2,2,2-trichloroethanol with Zn/AcOH to give 9b [27]. c) Enzymatic synthesis of symmetric

Ruthenium indenylidene “1^st generation” olefin metathesis catalysts containing triisopropyl phosphite

• Stefano Guidone,
• Fady Nahra,
• Alexandra M. Z. Slawin and
• Catherine S. J. Cazin

Beilstein J. Org. Chem. 2015, 11, 1520–1527, doi:10.3762/bjoc.11.166

• more active than 1 unless higher thermal stability is needed. Indeed, in the case of the malonate derivative 8, pre-catalyst 1 afforded the tri-substituted ring-closed product in 71% isolated yield. The similar structural and catalytic properties observed in the mixed phosphine/phosphite complex 1 and

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• demonstrated an interesting strategy to assemble [3.4]cyclophane derivative 197 by using the SM cross coupling and an RCM as key steps. The commercially available active methylene compound diethyl malonate was alkylated with a benzyl bromide derivative followed by the SM cross coupling to give dialkyl 196