Mn-mediated sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction towards annulated imidazo[1,2-a]pyridines

• Olga A. Storozhenko,
• Alexey A. Festa,
• Delphine R. Bella Ndoutoume,
• Alexander V. Aksenov,
• Alexey V. Varlamov and
• Leonid G. Voskressensky

Beilstein J. Org. Chem. 2018, 14, 3078–3087, doi:10.3762/bjoc.14.287

• oxidative conditions has been developed. The employment of Mn(OAc)3·2H2O or KMnO4 as stoichiometric oxidants allowed the use of a wide range of nucleophiles, such as nitromethane, (aza)indoles, pyrroles, phenols, pyrazole, indazole and diethyl malonate. The formation of the target compounds presumably

• diethyl malonate, providing compounds 14a–c in 40–58% yields. To conclusively reveal the scope of the reaction, we exploited N-cyanomethyl quaternary salts of fused thieno[2,3-c]pyridine 15 and 1-methyl-6-azaindole 16 in this transformation. Therefore, annulated chromenoimidazoles 17–20 were effectively

Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

• Eloi P. Coutant,
• Vincent Hervin,
• Glwadys Gagnot,
• Candice Ford,
• Racha Baatallah and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2853–2860, doi:10.3762/bjoc.14.264

• Scientifique, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France Université Paris Descartes, Sorbonne Paris Cité, 12 rue de l'École de Médecine, 75006 Paris, France 10.3762/bjoc.14.264 Abstract We have explored here the scope of the age-old diethyl malonate-based accesses to α-amino esters involving Knoevenagel

• condensations of diethyl malonate on aldehydes, reductions of the resulting alkylidenemalonates, the preparation of the corresponding α-hydroxyimino esters and their final reduction. This synthetic pathway turned out to be general although some unexpected limitations were encountered. The synthetic

• led us to require a large variety of α-amino esters as starting material. In view of the limitations we encountered in the use of ethyl nitroacetate to reach such variety [2], we have focused here on diethyl malonate-based methods as an alternative. Indeed, as we reviewed recently [3], this approach

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

• Glwadys Gagnot,
• Vincent Hervin,
• Eloi P. Coutant,
• Sarah Desmons,
• Racha Baatallah,
• Victor Monnot and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2846–2852, doi:10.3762/bjoc.14.263

• described in a following report [40], to overcome some of the limitations described here, we then focused on an exhaustive investigation of malonate-based strategies and reached an even more diverse set of α-amino esters. α-Amino esters from ethyl nitroacetate (4). Preparations of α-amino esters 10, 12 and

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• magnesium enolate of malonic acid half ester, prepared in situ from potassium methyl malonate, MgCl2 and triethylamine in acetonitrile, was added [24][25]. The acylation of magnesium methyl malonate by the preformed imidazole 3 led to the desired bifunctional starting material 4 in good yield (79

Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• compounds 6a and 6b by condensation with monoethyl malonate and monobenzyl malonate, in the presence of DCC and DMAP, in 80% and 83% yield, respectively. Starting from intermediates 6a and 6b, treatment with a tetrabutylammonium fluoride solution in diethyl ether at room temperature induced the cyclisation

• intermediate 13. Reagent and conditions: a) TEA, THF, 0 °C to rt, 2.5 h, 87%; b) monoethyl malonate (for 6a), monobenzyl malonate (for 6b), DCC, DMAP, CH2Cl2, 0 °C to rt, 24 h (for 6a), 12 h (for 6b), 6a: 80%, 6b: 83%; c) TBAF, Et2O, THF, 1-iododecane, rt, 24 h, 7a: 22%, 7b: 30%; d) CAN, CH3CN/H2O (3:1), 0 °C

D-Fructose-based spiro-fused PHOX ligands: synthesis and application in enantioselective allylic alkylation

• Michael R. Imrich,
• Jochen Kraft,
• Cäcilia Maichle-Mössmer and
• Thomas Ziegler

Beilstein J. Org. Chem. 2018, 14, 2082–2089, doi:10.3762/bjoc.14.182

• through their N- and P-moieties. They are usually prepared from amino acids or from the corresponding amino alcohols [9][13]. Some examples of literature-known PHOX ligands are shown in Figure 1 (1a–d). These ligands gave up to 96% ee by their application in allylic substitution with dimethyl malonate as

• -glucosamine and the sugar was linked to the aromatic system via an annulated oxazoline. Palladium complexes of 2 were used in allylic substitution of allyl acetates with dimethyl malonate as nucleophile and ee values from 69% to 98% were obtained [19]. Recently, we presented the synthesis of carbohydrate

• protective groups (5b) and one with ester groups (5i). As a model system for the Pd-catalyzed Tsuji–Trost reaction we chose diphenylallyl acetate 15 (Scheme 7) with dimethyl malonate. The latter allylic alkylation is well investigated and has often been used as a benchmark test for the selectivity of novel

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• cooled to 0 °C in the intermediate storage tank T5. The reaction mixture can pass through separator S1 (adsorption column) which is packed with MS 4 Å to remove the byproduct water. A solution of malonate and triethylamine in toluene are precooled to 0 °C in feed storage tanks and pumped to mixer M6

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• asymmetric Tsuji–Trost allylic alkylation of 1,3-diphenylprop-2-enyl acetate (33) with dimethyl malonate (34, Scheme 9). Both, good catalytic activity and enantioselectivity (ee values up to 86%) were obtained with the potassium cation. This was due to the more strongly interaction of the dimethyl malonate

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• dimethyl malonate and its nitro analogue gave benzoheptafulvalene derivatives 52 and 53 [50][63]. The condensation of 4,5-benzotropone (11) and anthrone (10H-anthracen-9-one) also afforded 4,5-benzo-tropyliden-anthron 54 in 65% yield [63]. Kitahara reported the synthesis of 1,2,3,4-tetrachloro-7,8

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• medicines and can be obtained by organocatalytic Michael additions. We show here the stereoselective synthesis of 4-methylpregabalin stereoisomers using a Michael addition of dimethyl malonate to a racemic nitroalkene. The key step of the synthesis operates as a kinetic resolution with a chiral squaramide

• malonate catalyzed by hydrogen-bond-donating organocatalysts (Scheme 2). We have also briefly investigated Meldrum´s acid as a donor, instead of dimethyl malonate, but we have obtained a complicated reaction mixture, which was difficult to purify. Therefore, we have focused our attention on the Michael

• addition of dimethyl malonate. An initial catalyst screening was performed in dichloromethane, based on our previous experiences with this type of Michael additions [18]. We have employed a range of squaramide and thiourea organocatalysts C1–C7 [18][27][28][29][30][31][32][33][34], as well as two newly

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• al. [102] reported a protocol for the efficient synthesis of pyrazolo[1,5-a]pyrimidine-5,7-dione (150) by the reaction of 5-aminopyrazole (126) with diethyl malonate (149). Pyrazolo[1,5-a]pyrimidine-5,7-dione (150) was chlorinated to give 5,7-dichloropyrazolo[1,5-a]pyrimidine (151) which subsequently

Transition-metal-free [3 + 3] annulation of indol-2-ylmethyl carbanions to nitroarenes. A novel synthesis of indolo[3,2-b]quinolines (quindolines)

• Michał Nowacki and
• Krzysztof Wojciechowski

Beilstein J. Org. Chem. 2018, 14, 194–202, doi:10.3762/bjoc.14.14

• -nitrobenzyl)malonate upon treatment with sodium hydroxide undergoes a multistep transformation resulting in 11-hydroxyindolo[3,2-b]quinoline-5-N-oxide (a) [9]. This approach is based on the first synthesis of the indolo[3,2-b]quinoline framework by Fichter and Boehringer in 1906 [10]. Indoxyl [11] and N,O

Nucleophilic dearomatization of 4-aza-6-nitrobenzofuroxan by CH acids in the synthesis of pharmacology-oriented compounds

• Alexey M. Starosotnikov,
• Dmitry V. Shkaev,
• Maxim A. Bastrakov,
• Ivan V. Fedyanin,
• Svyatoslav A. Shevelev and
• Igor L. Dalinger

Beilstein J. Org. Chem. 2017, 13, 2854–2861, doi:10.3762/bjoc.13.277

• ), C12–O3 1.3386(18), C11–C12 1.3687(19), C11–C14 1.450(2) Å) clearly indicate the enolic form of the compound. The reaction of 1 with less acidic diethyl malonate required the addition of 1 equivalent of Et3N. In this case product 13 was isolated in 78% yield (Table 1, entry 8). Again, due to the

• without added base while in case of diethyl malonate (pKa(H2O) 13.3) and TNT (pKa(H2O) 13.6) the addition of one equivalent of Et3N is required. In the latter case the formation of the adducts proceeds through the attack of the anion on C7. All other CH acids used exist mainly in enol form in polar

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• )malonate (24) to yield a mixture of two cyclic CF3 products, the main one being deprived of the chlorine atom (Scheme 20). Unfortunately, no more investigation was carried out on this type of cascade reactions. Trifluoromethylchlorosulfonylation of alkenes: It was previously evocated that the system

• example of such type of reaction was reported by Just and Hakimelahi in 1979 [49]. Their work was focused on the mono- or dichlorination of various carbon acids, in the pKa range between dialkyl malonate and methyl dichloroacetate, as well as certain nucleophiles, were reacted with

• the isolation of similar compounds starting from differently substituted β-lactams, notably carrying a malonate moiety linked to the nitrogen [57]. More recently, CF3SO2Cl also found to be an appropriate reagent for the asymmetric introduction of a chlorine atom onto several substrates. For instance

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• three water molecules which are released into bulk water upon mannose binding and thereby contribute to a favorable entropic effect. The cost to remove one water molecule from a calcium–malonate model system was calculated quantum mechanically (QM) to be 56.9 kJ/mol by Charifson et al. [64]. This is in

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

• Yaroslav D. Boyko,
• Valentin S. Dorokhov,
• Alexey Yu. Sukhorukov and
• Sema L. Ioffe

Beilstein J. Org. Chem. 2017, 13, 2214–2234, doi:10.3762/bjoc.13.220

• Stabilized enolates and their equivalents are the most studied C-nucleophiles in Michael addition reactions with nitrosoalkenes. A first systematic study in this area was done by Ohno and co-authors [13][23], who reported the addition of diethyl malonate and acetylacetone anions to cyclic nitrosoalkenes

• NSA1a–c generated from the corresponding α-chloroketones (2-chlorocyclohexanone oxime (1a), 2-chlorocyclooctanone oxime (1b) and 12-chloro-сyclododeca-4,8-dien-1-one oxime (1c)) upon the action of an excess of nucleophile (Scheme 2). It was found that oximes 1b and 1c react both with diethyl malonate

• proposed strategy of bicyclo[3.2.1]octanone 14 assembly is based on a combination of ring closing metathesis reaction and intramolecular addition of the malonate anion to a nitrosoalkene unit (Scheme 6). On the first stage, readily available chlorodiene 9 was subjected to a metathesis reaction with the

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• efforts had to be invested, before acid 21 could be efficiently obtained as shown in Scheme 4. Finally, after optimization of a reported procedure [73] the successful route employed a one-pot process involving a sodium hydride-mediated coupling of methyl malonate 19 with iodoform (20) followed by a

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