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

• ., benzaldehydes) and low-molecular-weight enolate nucleophiles, therefore, temperature regulation is vital for selectivity. This requirement for strict temperature control makes aldol reactions highly suited to flow processing conditions. In 2008, Tanaka et al. [96] disclosed several examples of aldol reaction in

• was evident (Scheme 3). Within the microreactor acetone was first deprotonated by merging with a 2.5 M sodium hydroxide stream at room temperature, then, after a residence time of just 45 seconds, the resultant enolate was introduced to a stream containing the aldehyde as a 5.5 M solution also in

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

• -aziridine in 50% yield under the same conditions. The transition state is proposed with a six-membered chair-like transition containing a four-membered metallocycle. In cis-aziridine the enolate of methyl α-bromoacetate has E-geometry and the trans-aziridine 8a has Z-geometry [32][33]. In the transition

• state, the metal cation of the enolate is being coordinated with both nitrogen and oxygen atoms of the sulfinimine [25][26] (Scheme 3). In 1999, Ellman and co-workers described the reduction of sulfinyl imines using sodium borohydride (NaBH4) [34] or o ʟ-selectride [35]. Davis–Ellman transition state

• consequence of the E stereochemistry of both the imine 14 and the enolate derived from bromoester 26 (Scheme 9). A two-step protocol carried out in a single synthetic operation was developed by Chen and Zhang to synthesize 3-substituted 2-chloroaziridines with relative cis configuration [71]. The reaction of

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• progresses under neutral conditions. The authors postulated that the vacancy on the square-planar Pd(II) species allows a faster alkene insertion in comparison to Pd(0). The cationic Pd(II) enolate exists as a dynamic mixture of C- and O-bound enolate and is highly susceptible to hydrolysis. This means that

• protonolysis of the O-bound enolate in the presence of PPh3 that leads to the regeneration of the catalytically active hydroxopalladium species and the addition product (Scheme 8) [43]. The presence of PPh3 ensures the preference of hydrolysis instead of a β-hydride elimination, which would lead to an

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

•  18). A sequence of reactions involving elimination of a proton from 83, treatment of 84 with an alkoxide, and protonation of the resulting enolate delivered thermodynamically favored equatorial ester 80 and 81. The highly diastereoselective Brønsted superacid-catalyzed Prins cyclization of

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 postulated mechanism indicates the formation of acylimine A from the lanthanum oxide-catalyzed reaction of aldehyde and 77. Further, addition of acyclic 1,3-diketone ester enolate to acylamine A form B which upon subsequent cyclization and dehydration resulted in the formation of desired products

Synthesis of β-triazolylenones via metal-free desulfonylative alkylation of N-tosyl-1,2,3-triazoles

• Soumyaranjan Pati,
• Renata G. Almeida,
• Eufrânio N. da Silva Júnior and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2021, 17, 762–770, doi:10.3762/bjoc.17.66

• to exist in twist-boat conformation. When R = H, the pseudoaxial approach of the nucleophile towards the β-position leading to the enolate intermediate VI (R = H) bearing pseudoequatorially oriented OTs group or the pseudoequatorial approach of the nucleophile leading to the intermediate VII (R = H

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

• corresponding acyclic or cyclic allylic amines in very good yields (see Supporting Information File 1 for details). Their subsequent α-deprotonation by LDA followed by treatment with chlorotrimethylsilane at −78 °C [81] resulted in clean C-silylation of the corresponding enolate providing silylacetamides 8a–m

• enolate formation from 8h,i with s-BuLi, a deuterium quenching experiment with D2O was performed. Analysis by 1H NMR spectroscopy revealed 87 and 91% deuterium incorporation, respectively, indicating that a deprotonation occurred, but the epoxide opening was hampered by the combination of a sterically

• diastereomeric ratios. To confirm enolate formation, lactam 12f was deprotonated by LDA at −78 °C and quenched with D2O, resulting in lactam 12f with 86% deuterium incorporation, but no change in the diastereomeric ratio. Spirolactams 12m,n were also subjected to epimerization (Scheme 4). The change of the

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

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

• followed by subsequent oxidation produced aldehyde (Z,Z)-61. After extensive unsuccessful efforts to produce enantiopure aldol fragment (Z,Z)-62 using the N-tosyl-ʟ-valine-derived oxazaborolidinone, the racemic synthesis of (Z,Z)-(rac)-62 was achieved by utilizing the lithium enolate of methyl isobutyrate

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

• potassium enolate to neutral η3-allylmolibdenum. The crude anionic intermediate 72 was treated with nitrosonium hexafluorophosphate in DME to provide bicyclic enone (−)-73 with 80% yield over two steps. Protection of the non-conjugated ketone (−)-73 as an acetal derivative occurred selectively to provide

• -sulfinimes (+)-95 and (+)-96 were added to a −78 °C solution of the N-methoxy-N-methylacetamide enolate 102, leading to Weinreb amides (+)-97 and (+)-98, respectively, with good yields and high diastereoisomeric excesses (Scheme 11). The reaction of (+)-97 and (+)-98 with five equivalents of methylmagnesium

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

• [52][53] with the allenyl rhodium to the enal and gives the allenyl rhodium species C. A Conia-ene-type reaction [54] between the Rhoda-enolate species and the allene of complex C produces the desired [3.3.0] bicycle D. Protonolysis [55][56][57] of complex D with the alcohol 110 gives bicyclic product

• cation, which is intercepted by the titanium enolate and results in the new C–C bond formation to give the five-membered carbocycle 169. Conclusion The all-carbon [3 + 2] cycloaddition, together with the [3 + 2] annulation, continue to be an attractive class of reactions for the synthesis of highly

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• epimerization is required. The requirement of additional reaction steps may explain the lower yield (31%) of this reaction. Note, that from the other three substrates, the product (rac)-27 was obtained in a yield of 52–54%. Since the enolate (rac)-T9 is all-equatorial, and consequently, the energy is lower than

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• trapped by enolate 160 in a chiral environment, provided by the PTC, to form a α-hydroperoxyl intermediate 161. Subsequent deoxygenation by another molecule of 160 forms two molecules of the α-hydroxylated products 162 in excellent yields and moderate enantioselectivities (11 examples, up to 88:12 er

•  24) [77]. Interestingly, this takes place without the need for an external photocatalyst and is proposed to proceed via an intermediate EDA complex 164, which, upon excitation, forms perfluoroalkyl radicals 163• that add to the enolate substrate that is coordinated to a chiral counterion 165 to give

• to generate diradical 177 that then adds to the alkene to form diradical 178. A SET between the ketyl radical and the α-carbonyl radical generates enolate intermediate 179, which after proton transfer regenerates the catalyst and releases the desired cyclisation product 180 in a moderate yield and

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• nucleophilic addition, the authors suggested the tentative mechanism depicted in Scheme 34. As shown, γ-fluoride loss from enolate I, formed after the conjugate Michael addition, would lead to the formation of difluoroenone II. This could in turn undergo a nucleophilic addition of water, followed by a retro

NHC-catalyzed enantioselective synthesis of β-trifluoromethyl-β-hydroxyamides

• Alyn T. Davies,
• Mark D. Greenhalgh,
• Alexandra M. Z. Slawin and
• Andrew D. Smith

Beilstein J. Org. Chem. 2020, 16, 1572–1578, doi:10.3762/bjoc.16.129

• stereogenic trifluoromethyl centers is through enantioselective addition of enolates or their equivalents to prochiral trifluoromethyl ketones (Figure 1A). Within this area, a common catalytic approach has utilized aliphatic ketones as enolate equivalents using prolinamide, cinchona, or hybrid catalysts that

• using NHCs, the azolium enolate has been widely used [27][28]. Methods to generate azolium enolates from a number of precursors have been reported, including the use of ketenes [29][30], α-functionalized aldehydes [31][32][33][34][35], enals [36][37][38], aryl esters [39][40][41][42], or aldehydes [43

• ][44][45] in the presence of an oxidant. As representative examples of the use of azolium enolates in reactions with trifluoroacetophenone derivatives, Ye and co-workers have shown that using disubstituted ketenes as azolium enolate precursors and NHC precatalyst 1 allowed access to trifluoromethyl

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli–Cushman protocol

• Aleksandar Pashev,
• Nikola Burdzhiev and
• Elena Stanoeva

Beilstein J. Org. Chem. 2020, 16, 1456–1464, doi:10.3762/bjoc.16.121

• ][14][20][21]. The mechanism of the reaction is still under debate with two prevailing versions in the literature (Scheme 2) [16][17][22][23][24]. The first reaction pathway includes the formation of an N-acyliminium ion 15, followed by a ring closure through an enolate ion 16. The other mechanistic

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• with zincate 11 using a variety of catalysts and different reaction conditions, was unsuccessful. However, coupling of 4-[bis(dimethoxybenzyl)difluoromethyl]benzyl bromide (14) with the lithium enolate of William`s lactone 15 gave the protected amino acid 16 in 80% yield. The desired protected amino

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• access various derivatives, such as 12 and 13, derived from the trapping and Baeyer–Villiger oxidation of 11, respectively, or compound 16, obtained via the ring opening reaction of 15 with an amine (Scheme 5). Taking the enolate intermediate derived from the addition of EtMgBr to coumarin as an example

• , it was shown that upon the treatment with an amine, this enolate produced the final chiral amide product with a good yield (82%) and ee (96%). While the methodology for the ACAs of Grignard reagents to chromones and coumarins has been established successfully, quinolones remained challenging

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• -α-hydroxy-β-keto esters in 81–93% yields and 39–75% ee (Scheme 41). The mechanism of this reaction involves the attack of the enolate paired with the chiral counter ion PTC to the singlet oxygen electrophile to give the hydroperoxide intermediate, which is converted to α-hydroxy-β-keto esters

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• . have contributed to the understanding of the mechanism of silylation reactions of unsaturated compounds. In their studies, it was possible, surprisingly, to isolate and characterize a β-silyl boron enolate complex 158. On the basis of experimental and NMR studies, they proposed that for α,β-unsaturated

• ketones, a 1,4-addition product was formed through a transient copper enolate, 157. With α,β-unsaturated esters, however, a carbon enolate, 160, is the intermediate. In order to maintain a catalytic cycle, iPrOH could be added to regenerate the active Cu species (Scheme 28). This study again proofed that

Copper-catalyzed O-alkenylation of phosphonates

• Nuria Vázquez-Galiñanes,
• Mariña Andón-Rodríguez,
• Patricia Gómez-Roibás and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2020, 16, 611–615, doi:10.3762/bjoc.16.56

• procedures involving a Mitsunobu reaction between 2-hydroxyalkyl phenyl selenides and phosphonic acid monoesters followed by an oxidation/elimination step [14] or reaction of an enolate with a phosphonic dichloride and subsequent treatment with an alcohol [15] (Scheme 1a). However, these procedures are

Copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters with chiral phenol–carbene ligands

• Shohei Mimura,
• Sho Mizushima,
• Yohei Shimizu and
• Masaya Sawamura

Beilstein J. Org. Chem. 2020, 16, 537–543, doi:10.3762/bjoc.16.50

• π-complex C undergoes 1,4-hydrocupration to afford copper enolate D. During our initial investigations, we observed configurational isomerization from 1a to (E)-1a when the reaction was conducted in the absence of alcoholic protonation reagents. This observation implied that the 1,4-hydrocupration

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• ) of potassium formate, which could not easily be removed without risking the decomposition of the enolate salt (Scheme 1). As the fluorine atom is part of a building block, harsh conditions for a late-stage fluorination can be avoided, and even products with sensitive functionalities are accessible

• ) and electron-withdrawing groups (compound 10l) were formed in nearly quantitative yields (95–99%). Only the 4-hydroxyphenyl derivative 10j was obtained in a moderate yield (69%) presumably due to competing polymerization of the enolate. The 4-chloro and 4-bromo derivatives (10m and 10n) were also

•  2). In the first reactions, only traces of the desired compound 13a were observed. Changing the temperature did not increase the yield. Acidic conditions were tested next but phenylhydrazine hydrochloride and acetic acid again gave only traces of 13a and polymerization of the enolate took place. To

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• catalytic species, the resulting metallic enolate intermediate can also react with the starting material to form the aldol byproduct, significantly altering the yield of the expected 1,4-product (Scheme 1). The first successful copper-catalyzed ECA to α,β-unsaturated aldehydes with organozinc and Grignard

• –86%) and yield (44–63%) remained decent. The efficiency of TolBINAP (L3)/CuI was also demonstrated in the ECA of Grignard reagents to the 4-chloro-α,β-unsaturated thioester 22 [31]. Interestingly, the presence of the internal chloro leaving group allowed a powerful tandem conjugate addition–enolate

• /enolate trapping was also studied, providing the trans-cyclopentane product 56 as a single diastereoisomer (92% ee). In 2018, the same authors reported the 1,6- and 1,4-additions of various Grignard reagents to a wide scope of conjugated dienyl amides (Scheme 22) [51]. Interestingly, the authors observed

Why do thioureas and squaramides slow down the Ireland–Claisen rearrangement?

• Dominika Krištofíková,
• Juraj Filo,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2019, 15, 2948–2957, doi:10.3762/bjoc.15.290

• solvent and the amine’s structure [22][23]. The decomposition of the enolate is one of the side reactions, which can be suppressed by chelation. The chelation-stabilized enolates are more stable than the corresponding silyl ketene acetals, and they are capable of a direct rearrangement [24]. The chelation

• -controlled Ireland–Claisen rearrangement of O-protected allylic glycolate esters proceeded with moderate yields and diastereoselectivities of up to 20:1 [25]. An asymmetric ester-enolate-Claisen rearrangement was achieved by using aluminum-chelate-bridged enolates and proceeded with high yields and

• the corresponding acid 3a in 63% yield at rt (Table 1, entry 1). At a higher temperature, the product yield decreased (Table 1, entry 2). The reaction of the related (E)-but-2-en-1-yl propionate (1b) gave acid 3b under similar conditions with slightly lower yields. The rearrangement of lithium enolate

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• oxidation by raising the energy of the HOMO upon enolate formation. Upon constant current electrolysis of a mixture of 85 and 86 in an undivided ElectraSyn 2.0 cell in presence of 2,6-lutidine as an external base and catalyst 87, products with tertiary carbon stereocenters as well as all-carbon quaternary

• to 2-acylimidazole derivatives 94 generates the Lewis acid/enolate complex 100 upon deprotonation (Scheme 35). This is followed by the formation of intermediate 101 by electrolysis-induced SET oxidation. In a parallel electrochemical cycle, benzylic radical species 95 was delivered by the anodic

• asymmetric reduction of 135 using enolate reductase that afforded the corresponding chiral acid 136 in 95% yield and 95% ee. It has been shown that the cofactor NADH is oxidized during this process and can be regenerated using methyl viologen 137 as a reductive mediator (Scheme 43) [78]. In 1997, Yoneyama