Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• , was the only example reported of a quaternary carbon center synthesis (Scheme 12). The observations that no reaction was detected in the absence of AgOCl and that only an aza-Michael adduct was observed in the absence of the gold(I) complex led the authors to propose that the silver(I) salt promoted

Breaking paracyclophane: the unexpected formation of non-symmetric disubstituted nitro[2.2]metaparacyclophanes

• Suraj Patel,
• Tyson N. Dais,
• Paul G. Plieger and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2021, 17, 1518–1526, doi:10.3762/bjoc.17.109

• observed (Figure 6). As with the oxidation, we assume that the lower deck blocks approach from one face. Protonation of the adduct also occurs anti to the para ring. We suspect that this second addition favors the trans product over the cis rather than the para ring influencing the approach of the proton

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• Guareschi imides, which, under the original protocol, is limited to ketones as the carbonyl component. When aldehydes are used, the adduct is aromatized to the corresponding 2-hydroxypyridone [50][51]. Finally, a modification of the type-IV Guareschi reaction that involves the condensation of two moles of

• reacts with aldehydes and eventually regenerates a triphenylmethane dye from the sulfite adduct [22]. The study of old color reactions has not only mechanistic interest but can lead to new drug candidates, as shown by the

A new glance at the chemosphere of macroalgal–bacterial interactions: In situ profiling of metabolites in symbiosis by mass spectrometry

• Marine Vallet,
• Filip Kaftan,
• Veit Grabe,
• Fatemeh Ghaderiardakani,
• Simona Fenizia,
• Aleš Svatoš,
• Georg Pohnert and
• Thomas Wichard

Beilstein J. Org. Chem. 2021, 17, 1313–1322, doi:10.3762/bjoc.17.91

• both profiling and imaging MS spectra as the [M + Na]+ adduct at m/z 165.0633. Ectoine was mainly found around the rhizoid in elevated amounts. Thus, Roseovarius sp. MS2 became visible in the rhizoidal zone and on the thallus due to the exclusive production of ectoine within the tripartite community

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• -nucleoside reverse transcriptase inhibitor (NNRTI) doravirine (49) in flow (Scheme 5) [100]. The aldol reaction of an aromatic ester 44 with a vinylogous ester 45 was achieved in a continuous manner, yielding the hydroxyl adduct, 46, in 85% yield within just a 15 second residence time. Here, a slightly

• of the catalyst in less polar solvents (Scheme 11). Thus, a stream of 2,6-dichlorobenzaldehyde (70) and cyclohexanone (65) along with 10 mol % of AcOEt and 3 mol % H2O were directed as a flow stream into the loaded column to partake in the aldol reaction to furnish adduct 71 in 95% yield and

• (Scheme 12) [113]. The reactor output reached a maximum conversion of 64%, generating a 1:1 ratio of the aldol adduct 39 and the further condensation product 72. It was also shown that the selectivity for 39 could be improved by increase the flow rate, although this also coincided with a lower conversion

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• dissociation energy (ΔΔG) by 10.6 kcal/mol. The formation of the neighboring group stabilized the oxocarbenium ion (dioxolenium ion) and its reaction with alcohol leads to the experimentally observed glycosides and the FSO2H adduct. We assume that due to the formation of the latter also substrates, which do

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• an intimate ion pair 51. The proximal addition of a bromide ion to 51 produces axial adduct 56 exclusively. However, when SnBr4 is used as a Lewis acid, oxocarbenium ion 52 is formed via 50. The counterion SnBr4− being much less nucleophilic than the Br− ion allows the formation of a solvent

• formal 2-oxonia-[3,3]-sigmatropic rearrangement. Furthermore, Markó and co-workers successfully synthesized 2,6-anti-configured THP starting from allylsilane 245, following diethylaluminium chloride-promoted ene reaction and condensation with an aldehyde 246 [102]. Expected ene adduct 247 was obtained as

Highly regio- and stereoselective phosphinylphosphination of terminal alkynes with tetraphenyldiphosphine monoxide under radical conditions

• Dat Phuc Tran,
• Yuki Sato,
• Yuki Yamamoto,
• Shin-ichi Kawaguchi,
• Shintaro Kodama,
• Akihiro Nomoto and
• Akiya Ogawa

Beilstein J. Org. Chem. 2021, 17, 866–872, doi:10.3762/bjoc.17.72

• inhibited the desired phosphinylphosphination (see, alkyne 2f), probably because of the decomposition of Ph2P(O)PPh2. Furthermore, an electron-deficient alkyne such as methyl propiolate (2h) failed to provide the desired adduct (3h) [61]. 3-Phenyl-1-propyne (2i) and cyclohexylacetylene (2j) gave 3i and 3j

• phosphinylphosphination of some internal alkynes, 2p and 2q, with Ph2P(O)PPh2, but did not afford any adduct (the starting alkynes were recovered unchanged) (Scheme 4). This is most probably because the internal alkynes are sterically bulkier than terminal alkynes, and therefore, the addition did not proceed (Scheme 4

• was complete, sulfur (3 equiv) was added under inert atmosphere and then the mixture was stirred at 60 °C for 6 h to provide the stable adduct 3. The purification of the products was performed by silica gel column chromatography using isohexane/MeOAc as an eluent. Radical addition of Ph2PPPh2 and Ph2P

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• the involvement of an elementary formation of Knoevenagel adduct A from the reaction between the aldehyde and 11. This adduct undergoes an intermolecular Michael addition to naphthylamine resulting in the formation of B. A subsequent intramolecular nucleophilic cyclization leads C followed by

• proposed two different mechanisms in which the first mechanism involved two subsequent reactions. The first one being a Knoevenagel condensation between aromatic aldehyde and ethyl cyanoacetate to yield a Knoevenagel intermediate A which upon subsequent reaction with benzamidine, forms Michael adduct B. A

• consecutive ring closure yields the desired product 75 aided by the attack of nitrogen lone pair in Michael’s adduct C via a sequential ethanol elimination (E) from D followed by aerial oxidation of intermediate F. Another proposed mechanism follows the formation of imine derivative G produced by the reaction

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• of N-heterocyclic compounds. In 2017, Wu and colleagues [58] uncovered the use of the bis(sulfur dioxide) adduct of DABCO, 1,4-diazabicyclo[2.2.2]octane·(SO2)2, as sulfone source in the EDA complex formation by 4-methyl-1-(p-tolyl)pentan-1-one O-(2,4-dinitrophenyl)oxime (11) towards the

• -bond adduct. The first light-promoted three-component reaction has been realized by a halogen-bond adduct, forming perfluoroalkylated pyrimidines 26 (Scheme 8). A variety of perfluorinated chains were assembled with methylene compounds and guanidines or amidines, giving the corresponding

• perfluoroalkyl iodide form a halogen-bond adduct, and then light-induced electron transfer happens in order to give a perfluoroalkyl radical. The protocol can realize alkene- and alkyne iodide perfluoroalkylation and C–H perfluoroalkylation of electron-rich heteroaromatic hydrocarbons, providing a novel protocol

Synthesis of dibenzosuberenone-based novel polycyclic π-conjugated dihydropyridazines, pyridazines and pyrroles

• Ramazan Koçak and
• Arif Daştan

Beilstein J. Org. Chem. 2021, 17, 719–729, doi:10.3762/bjoc.17.61

• cycloaddition reaction, a retro Diels–Alder reaction of the resulting adduct, and a final 1,3-prototropic hydrogen shift took place to afford cycloadducts 3a,b [55] and 3c–f (87–96% yield) (Scheme 1 and Table 1). As shown by the reaction conditions in Table 1, the reactions of tetrazine derivatives with

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• for 12m. However, the coupling diastereoselectivity with TEMPO (3) amounted to 4:1 for the trans diastereomers 12nA,B and exclusive for the cis isomer 12nC. The relative configuration of diastereomer 12nA was unequivocally established by X-ray crystallography of the hydrochloride adduct of the keto

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• CBr4 or I2, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or NaH as the base, and a malonate-derived substrate. The adduct is synthesized in a slightly higher yield by direct treatment of fullerene with malonates. As noted above, a decrease in the strain of the fullerene core is the driving force of its

• ethereal solution of diazomethane in toluene at 0 °C resulted in pyrazoline derivative C [81]. The adduct isolated chromatographically was exposed to ultraviolet (UV) irradiation for 25 min at 25 °C in a quartz tube. The resulting isomers 3 and 4 were separated by reversed-phase high-performance liquid

• adduct 8 and diethyl dicarboxymethanofullerene 11 were synthesized in Rh2(OAc)4-catalyzed reactions. Using Rh2(OAc)4, the selectivity of the process was improved, and the yield of the target products slightly increased to 42 and 32%, respectively [85]. The ability of derivatives to effectively preserve

Valorisation of plastic waste via metal-catalysed depolymerisation

• Francesca Liguori,
• Carmen Moreno-Marrodán and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2021, 17, 589–621, doi:10.3762/bjoc.17.53

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• , respectively) gave the two highest results, but the use of dioxane is best avoided due to its toxicity. Except for hexane (only 6% ee, Table 1, entry 13), which resulted in an almost racemic product presumably due to solubility issues, all other solvents afforded the target SMA adduct with similar moderate ee

• the chalcone derivatives employed in the model reaction, the best result in terms of enantioselectivity was attained with 4-methyl-substituted chalcone, which allowed the synthesis of the corresponding SMA adduct 12d with an excellent ee of 91% (Table 3, entry 4). Good to moderate results were

• unexpected result, we decided to revisit the solvent screening. For this purpose, the sulfa-Michael addition of naphthalene-1-thiol to 11c was carried out again in toluene, dioxane, DCM and THF (Table 4). In DCM, 93% ee was attained for adduct 12c. In the light of this striking result, we decided to repeat

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• that is used as a hemiaminaloate adduct [Me2NCH(O)CF3]- (Scheme 1b) [19][20][21][22][23][24][25][26][27][28]. Although the taming CF3 anion had been an elusive problem for decades, it has been dramatically progressed in recent years by the substantial works by Grushin [51][52][53] and Prakash [54]. Our

• . Trifluoromethyl ketones. a) Hydrolysis of trifluoromethyl ketones. b) Selected examples of biologically active trifluoromethyl ketones. Chemistry of the CF3 anion generated from HCF3. a) Decomposition of the trifluoromethyl anion to difluorocarbene and fluoride. b) A hemiaminaloate adduct of CF3 anion to DMF. c

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• . Heating the mixture at 60 °C for 4 h does not result in any change of the color from that characteristic of o-quinone 4. After cooling of the solution red crystals of adduct 8 were isolated (see Figure 2 and Figure S6 in Supporting Information File 1). The X-ray diffraction study reveals that adduct 8 is

• -quinone 4. Each o-quinone molecule bridges two adjacent sodium ions. The bond lengths distribution in the o-quinone moiety in 8 is typical of sterically hindered o-quinones (Table S1 in Supporting Information File 1). According to 1H and 13C NMR spectroscopy data, adduct 8 in CD3OD solution exists as

• stoichiometric mixture of 4 and monosodium salt of hfac, so that adduct 8 forms in a crystal phase only. Our studies indicate that the interaction of 4 with stable gem-dithiolates, such as sodium trithiocarbonate, malononitrile gem-dithiolate or 2,6-di-tert-butylphenol gem-dithiolate proceeds in a predictable

Insight into functionalized-macrocycles-guided supramolecular photocatalysis

• Minzan Zuo,
• Krishnasamy Velmurugan,
• Kaiya Wang,
• Xueqi Tian and
• Xiao-Yu Hu

Beilstein J. Org. Chem. 2021, 17, 139–155, doi:10.3762/bjoc.17.15

• between them. These nonbonding interactions could allow the double bonds to be placed at an optimal distance for the efficient [2 + 2]-photoadduct. However, this adduct could not be observed in the absence of the metal cation, indicating the importance of the preorganization of the substrates with Ba2

Facile preparation and conversion of 4,4,4-trifluorobut-2-yn-1-ones to aromatic and heteroaromatic compounds

• Takashi Yamazaki,
• Yoh Nakajima,
• Minato Iida and
• Tomoko Kawasaki-Takasuka

Beilstein J. Org. Chem. 2021, 17, 132–138, doi:10.3762/bjoc.17.14

• ]. As expected for this model system, a very efficient addition was observed within a period of 0.5 h at 0 °C, leading to an isolated yield of 69% for the adduct 3aa when 1.5 equiv of acetylacetone and NaH in Et2O were used (Table 2, entries 1−3), which unambiguously demonstrated the high potency of 2a

• to proceed under the action of a catalytic amount of a base, and only 2 mol % of t-BuOK led to the formation of the desired adduct 3aa as a sole stereoisomer in 84% isolated yield under the same reaction conditions (Table 2, entries 6−8). The E-stereochemistry of 3aa was deduced from the NMR data of

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• %). Deprotection of the TBDMS ether of stannane 40 with tetra-n-butylammonium fluoride (TBAF) in THF and then subsequent Swern oxidation of the crude alcohol gave aldehyde 41 in 71% yield. The aldehyde 41 was treated with ethyl isobutyrate (42) in the presence of LDA to afford the aldol adduct (Z)-(rac)-43 in the

• diastereoisomers. Then, the key aldol reaction of 123 with silyl enol ether 53 under optimized Mukaiyama–Kiyooka conditions, followed by TIPS deprotection, afforded adduct (3R)-(+)-11 in 63% yield and with 94% ee. Ester hydrolysis followed by acetylation of (3R)- (+)-11 produced acid derivative (+)-76 [50] in 87

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• tricyclic adduct (+)-23b, a precursor to (−)-adaline (1). This methodology, based on the synthesis of optically active β-sulfinyl nitrones, was proved to be efficient in the synthesis of (+)-euphococcinine (2) in 7 steps from piperidine (17), in an overall yield of 2.1%. Specific rotation for (+)-2 was [α

• –dehydration reactions, via intermediate anti-aldol (−)-67 (Scheme 8). The addition of Grignard reagent to the enone (E)-(−)-68 occurred anti to the group TpMo(CO)2 to give adduct (E)-69, which was used in the next step without purification. The treatment of this adduct with HCl in dioxane promoted

Amine–borane complex-initiated SF₅Cl radical addition on alkenes and alkynes

• Audrey Gilbert,
• Pauline Langowski,
• Marine Delgado,
• Laurent Chabaud,
• Mathieu Pucheault and
• Jean-François Paquin

Beilstein J. Org. Chem. 2020, 16, 3069–3077, doi:10.3762/bjoc.16.256

• -containing adduct, with yields of 80% and 89% with EtOAc and hexane, respectively (Table 3, entries 3 and 4). Finally, we performed the reaction in hexane with no amine–borane complex added, and only trace amounts of the final compound 2a were detected (Table 3, entry 5). We next wondered if it could be

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

• ] cycloaddition of activated octalone 26 and the trimethylenemethane precursor 27 selectively produced adduct 28 in 98% yield, which is a synthetic precursor of 3β-hydroxykemp-7(8)-en-6-one (7). Another two syntheses of (±)-hirsutene (14), after Little’s pioneering work [22], were accomplished by Krische [25] and

• give 56 in 83% yield over two steps [31] (Scheme 2C). This transformation was rationalized as follows: freshly prepared 52b was converted to diazo 53, which was subjected to [3 + 2] cycloaddition to give adduct 54. Formation of diyl 55 from 54 and subsequent [3 + 2] cycloaddition produced the

• and co-workers disclosed the palladium-catalyzed intermolecular carboxylative TMM [3 + 2] cycloaddition [36] (Scheme 3). Exposure of coumarin 61 to the silyl-substituted TMM precursor 62 in the presence of a catalytic amount of Pd(PPh3)4 afforded adduct 63 in 81% yield as a single diastereomer (Scheme