Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• Indonesian sponge Haliclona sp. [108]. Their synthesis takes advantage of the same tandem procedure that gives β-ketoester 219. The asymmetric conjugate 1,4-addition and subsequent acylation provided good stereocontrol and the authors could revise the thus far incorrectly assigned configuration of the target

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• -tricarbonyl compound 108 to set two stereogenic centers and correct one via an intramolecular aldol addition (108 → 109; Scheme 18) [34]. The vic-tricarbonyl compound 108 was synthesized via DMDO oxidation from α-diazo-β-ketoester 107, which was easily accessible from 5-methoxy-4H-chromen-4-one (106). The

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

• Md Imran Hossain,
• Md Imdadul H. Khan,
• Seong Jong Kim and
• Hoang V. Le

Beilstein J. Org. Chem. 2022, 18, 446–458, doi:10.3762/bjoc.18.47

• reaction To a solution of the 1,3-diketone, β-ketoester, or β-ketoamide (0.5 mmol, 1 equiv) in methanol was added water, phenyl hydroximoyl chloride (1 equiv), and DIPEA (3 equiv) at room temperature (total volume of methanol and water = 15 mL; 95% water, 5% methanol). The reaction mixture was stirred for

Synthesis of 5-unsubstituted dihydropyrimidinone-4-carboxylates from deep eutectic mixtures

• Sangram Gore,
• Sundarababu Baskaran and
• Burkhard König

Beilstein J. Org. Chem. 2022, 18, 331–336, doi:10.3762/bjoc.18.37

• -unsubstituted 3,4-dihydropyrimidinone-4-carboxylate derivatives by employing oxalacetic acid as a β-ketoester equivalent in the presence of TFA via a Biginelli reaction [23]. Lam and Fang reported the same synthesis under microwave conditions [24]. Very recently, Kambappa and co-workers reported a one-pot

• synthesis of 5-unsubstituted dihydropyrimidinone-4-carboxylate using gem-dibromomethylarene, oxalacetic acid, and urea [25]. Here the gem-dibromomethylarene moiety serves as an aldehyde equivalent. In addition, utilizing aromatic ketones as a β-ketoester equivalent, the synthesis of 5-unsubstituted DHPM

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• -ketol rearrangement to 59. Note that this reaction took advantage of the thermodynamically preferred conversion of an α-ketoester to a β-ketoester seen in other examples in this review. Although not technically a tandem reaction due to the need to add a reagent to continue the cascade, the sequence of

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• undergoes radical addition with the N-substituted maleimide (Scheme 25). In 2017, Wu and co-workers [94] reported the α-amino C−H functionalization of aromatic amines 51 with nucleophiles, including arynes or aromatic olefins 52, indoles, acyclic β-ketoester 53, and β-diketone 54 (Scheme 26). Mechanistic

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• proton of the enolizable β-ketoester 49 and thus activating the nucleophilic species. This enolate then adds to the cationic substrate from in situ upon halide abstraction of α-chloro amino acid derivatives 48 by the thiourea moiety of the bifunctional catalyst (Scheme 10c, key intermediate), leading to

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• of further C(7a)-hydroxylated bacterial pyrrolizidines and related molecules. Pyrrolizidine 14 (Scheme 1), the key intermediate in Snider’s improved route to jenamidine A and Bode’s preparation of pyrrolizixenamides A (9) and D (12), is formed by N-cyclization onto the nitrile group in cyano-β

• -ketoester 13. The appended ester functionality in 14 has, at some point, to be removed, as its presence complicates a potential application to the (2-methyl-substituted) legonmycins, and it exerts a potentially stabilizing electronic effect on pyrrolic intermediates that could be unhelpful in downstream

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• -workers in 2014 [49] (Scheme 9A). The synthesis began with the conversion of ketone 112 into alcohol 113 in four steps, which involved a hypervalent iodine-mediated ring expansion [60]. A two-step synthesis from 113 gave epoxide 114. Epoxide 114 was converted to the corresponding β-ketoester and

One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

• Giovanna Bosica,
• Kaylie Demanuele,
• José M. Padrón and
• Adrián Puerta

Beilstein J. Org. Chem. 2020, 16, 2862–2869, doi:10.3762/bjoc.16.235

• equivalents of the β-ketoester ethyl acetoacetate (2) with benzaldehyde (1a) and ammonia (Scheme 1) [11]. This procedure was later optimized over the years using different substrates by varying the β-ketoesters and aldehydes in order to prepare a larger array of 1,4-dihydropyridines (1,4-DHPs) [12]. In

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

• -activated acylimidazole derivative was then converted to a β-ketoester containing a two carbon atom-elongated side chain than that of the starting material. A Knorr cyclization of the bifunctional 1,3-dicarbonyl compound with hydrazine and its monosubstituted derivatives in AcOH under microwave heating

• conditions led to the regioselective formation of 17-exo-heterocycles in good to excellent yields. The suppression of an acid-catalyzed thermal decarboxylation of the β-ketoester and thus a significant improvement in the yield of the desired heterocyclic products could be achieved by the preliminary

• preliminary results concerning the cancer selectivity of the selected agents. Results and Discussion Synthetic studies The steroidal β-ketoester precursor 4, suitable for the attempted heterocyclization reaction with hydrazines was synthesized from commercially available pregnenolone acetate (1) via a

Studies towards the synthesis of hyperireflexolide A

• G. Hari Mangeswara Rao

Beilstein J. Org. Chem. 2018, 14, 2106–2111, doi:10.3762/bjoc.14.185

• in its tautomeric enol form 7, observed in the 1H NMR spectrum after column chromatographic purification (6 and 7 were not separated) as represented in Scheme 2 [33]. In order to check the feasibility of the alkylation reaction of γ-lactone-fused β-ketoester 6, initially a mixture of 6 and 7 was

• subjected to methylation using 1.1 equiv of K2CO3 in the presence of methyl iodide (MeI). The α-methylated β-ketoester 8 was obtained in good yield. In the 1H NMR, 8 showed a signal at 3.70 ppm as doublet for C-10 (ring junction) proton confirming the selective methylation at C-8. Further, installation of

• the methyl group at C-10 was achieved by treatment of 8 with 1.1 equiv of K2CO3 in the presence of MeI to give bis-methylated γ-lactone-fused β-ketoester 9 in 72% yield (Scheme 3). These results demonstrated that regioselective alkylation at the two sites were possible. Notably, one diastereomeric

A survey of chiral hypervalent iodine reagents in asymmetric synthesis

• Soumen Ghosh,
• Suman Pradhan and
• Indranil Chatterjee

Beilstein J. Org. Chem. 2018, 14, 1244–1262, doi:10.3762/bjoc.14.107

• more effective chiral iodonium salts 16 which were used for the α-arylation of β-ketoester 86 to deliver α-arylated β-ketoesters 87 with moderate enantioselectivity (Scheme 17) [63]. This was the first example of an asymmetric α-arylation of β-ketoesters using hypervalent iodine reagents. A more

Synthesis of pyrazolopyrimidinones using a “one-pot” approach under microwave irradiation

• Mark Kelada,
• John M. D. Walsh,
• Robert W. Devine,
• Patrick McArdle and
• John C. Stephens

Beilstein J. Org. Chem. 2018, 14, 1222–1228, doi:10.3762/bjoc.14.104

• reaction conditions were chosen to match the already developed microwave-assisted synthesis of the 5-aminopyrazoles. A solution of the β-ketonitrile in methanol was treated with hydrazine and heated to 150 °C under microwave irradiation for 5 min. The β-ketoester and acetic acid were then simply added to

• conventional heating. When a mixture of previously isolated 5-aminopyrazole 2a, β-ketoester, and acetic acid were heated under conventional refluxing conditions for 18 h, the product pyrazolo[1,5-a]pyrimidinone 3a could only be isolated in a 25% yield. As expected, heating the reaction mixture for 2 h at

• reflux gave a lower isolated yield of 11%. A one-pot procedure under conventional refluxing conditions was also carried out in direct comparison with the microwave method, i.e., a solution of the β-ketonitrile in methanol was treated with hydrazine and refluxed for 5 min. The β-ketoester and acetic acid

Reagent-controlled regiodivergent intermolecular cyclization of 2-aminobenzothiazoles with β-ketoesters and β-ketoamides

• Irwan Iskandar Roslan,
• Kian-Hong Ng,
• Gaik-Khuan Chuah and
• Stephan Jaenicke

Beilstein J. Org. Chem. 2017, 13, 2739–2750, doi:10.3762/bjoc.13.270

• and amides have been developed, controlled by the reagents employed. With the Brønsted base KOt-Bu and CBrCl3 as radical initiator, benzo[d]imidazo[2,1-b]thiazoles are synthesized via attack at the α-carbon and keto carbon of the β-ketoester moiety. In contrast, switching to the Lewis acid catalyst

• ). However, only trace amounts of 3i were obtained for 2-aminobenzothiazoles bearing the strongly electron-withdrawing CF3 group. It was encouraging to see both that the benzoxazole and thiazole derivatives reacted well with their respective β-ketoester coupling partners to form 3j and 3k with 84% and 92

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• containing a trifluoromethyl group at C-2 and a p-halogen-substituted and non-substituted phenyl-1,2,3-triazole moieties. The synthesis of 2-(trifluoromethyl)-6-phenylquinolone was achieved by Conrad–Limpach reaction of a primary aromatic amine with a β-ketoester [37][38]. Namely, thermal condensation of 4

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• electron-withdrawing trifluoromethyl substituent was an exception to this (7) [31]. For this case, crude 19F NMR after the first step shows a 41% conversion, suggesting that the pyrazolone formation is the limiting factor in this example. An alkyl β-ketoester (ethyl acetoacetate) was also used, affording

• methyl substituted difluoropyrazolone 12 in modest yield. Finally, an α-substituted β-ketoester was successfully converted to the pyrazolone before monofluorination using one equivalent of Selectfluor to prepare pyrazolone 13, also in moderate yield. In general the optimised approach seems to apply to a

Iodoarene-catalyzed cyclizations of N-propargylamides and β-amidoketones: synthesis of 2-oxazolines

• Somaia Kamouka and
• Wesley J. Moran

Beilstein J. Org. Chem. 2017, 13, 1823–1827, doi:10.3762/bjoc.13.177

• 2-oxazoline formation through the iodoarene-catalyzed cyclization of β-amidoketones 5. These are readily prepared by alkylation of the corresponding β-ketoester followed by decarboxylation (Scheme 4) [40][41]. The cyclization of β-amidoketones 5 was successful with the same conditions as

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

• 3 can then react with the nucleophilic α-carbon atom of β-ketoester 4 to an open chain ureide 5. Subsequent ring closure results in a hexahydropyrimidine intermediate 6. In the last step, the irreversible elimination of water forms the thermodynamically favored DHMP product 7. This accepted

• mechanism was supported by spectroscopic data. However, alternative mechanisms are discussed in the literature [17][18]. In the so called enamine route, urea 2 and the β-ketoester 4 form an enamine in the first reaction step. Subsequently, the enamine reacts with the aldehyde 1 [19]. A third mechanism

• discussed, is the Knoevenagel type reaction between the aldehyde 1 and β-ketoester 4 followed by a subsequent reaction with urea 2 [20]. The Passerini reaction The Passerini reaction was discovered in 1921 by Mario Passerini and is a three-component reaction between a carboxylic acid 8, a carbonyl compound

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• 2015. Review 1 Biginelli condensation The classical Biginelli condensation involves the reaction of an aldehyde 1 with urea (2) and a β-ketoester 3 under acidic conditions in refluxing ethanol to yield 3,4-dihydropyrimidin-2-one derivatives 4 (Scheme 1) [24]. Although, a large number of CH-acidic

Catalytic asymmetric formal synthesis of beraprost

• Yusuke Kobayashi,
• Ryuta Kuramoto and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2015, 11, 2654–2660, doi:10.3762/bjoc.11.285

• yield (Table 1, entry 8). With both the AIOM adducts 5 and 6 in hand, we next investigated the construction of the tricyclic core (Scheme 3 and Scheme 4). The cross-Claisen condensation of 6 with lithium tert-butyl acetate afforded the corresponding β-ketoester, which was then treated with 2-azido-1,3

A simple and efficient method for the preparation of 5-hydroxy-3-acyltetramic acids

• Johanna Trenner and
• Evgeny V. Prusov

Beilstein J. Org. Chem. 2015, 11, 323–327, doi:10.3762/bjoc.11.37

• ] variant of Lacey–Dieckmann [8] condensation (Scheme 1) [9][10]. Reaction of either β-ketoester 4 or Meldrum’s acid derivative 9 with suitably protected glycine esters (5,6,10), followed by base-induced condensation furnished the desired tetramic acid model compounds as crystalline solids after treatment

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• (±)-32 in racemic form. We anticipated the interception of (−)-32 [57] in Danishefsky’s route using enantioselective palladium-catalyzed allylic alkylation to set the quaternary stereocenter. The formal total synthesis of (−)-dysidiolide (29) commenced with known allyl β-ketoester 4 (Scheme 7), which was

• -cyclohexanedione (40), which was converted to isobutyl vinylogous ether 41 under acid promotion (Scheme 9) [65]. The β-ketoester 42 was prepared using a two-step sequence of acylation and alkylation, then treated with the (S)-t-Bu-PHOX catalyst system (with [Pd(dmdba)2]) to generate (+)-43 in 86% ee. The challenge

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• to allyl diethylphosphonoformate (114) afforded β-ketoester 115, which in turn was condensed with commercially available azetidinone 116 to give 117 as a mixture of diastereomers. Protection of the nitrogen with TBS triflate followed by deprotection of the allyl carboxylate with formic acid under

Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

• Patrick Rabe,
• Tim A. Klapschinski,
• Nelson L. Brock,
• Christian A. Citron,
• Paul D’Alvise,
• Lone Gram and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2014, 10, 1796–1801, doi:10.3762/bjoc.10.188

• . Oxidative cleavage of the glycol with NaIO4 resulted in a β-ketoester aldehyde that upon treatment with silica gel underwent an intramolecular aldol condensation to a mixture of 10a and 11a that were separable by column chromatography. Oxidation with DDQ gave tert-butyl tropone-2-carboxylate (12a) that was

• cycloheptanone derivatives with rigorously simplified structures as compared to TDA were included in this study. The β-ketoester 27 containing a Michael acceptor was synthesised from methyl cycloheptanone-2-carboxylate (26) by oxidation with Cu(OAc)2 and Pb(OAc)2 according to a known procedure [16]. The compound