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

• expense of the olefin double bond. Review Olefin activation by transition metals Transition metals can act as π-acid catalysts in olefin double bond activation, as they weaken the alkene double bond through coordination to allow a nucleophilic attack on the sp2 carbon to form an alkylmetal intermediate

• than Pd(II)-catalytic types have also been explored. Pd(II)-catalyzed hydroalkylation reactions The σ-alkylpalladium species formed after a carbon nucleophilic attack on an alkene double bond (Scheme 1) have a marked tendency to undergo a hydride β-elimination process that leads to oxidative coupling

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

• is formed than we isolate. The compound can react further. Simply treating it with silica and methanol during filtration leads to the conjugate addition of methanol to the doubly activated alkene to give a cyclohexenone cyclophane 14 (Scheme 3). Attempting to force this reaction with acid leads to a

Cascade intramolecular Prins/Friedel–Crafts cyclization for the synthesis of 4-aryltetralin-2-ols and 5-aryltetrahydro-5H-benzo[7]annulen-7-ols

• Jie Zheng,
• Shuyu Meng and
• Quanrui Wang

Beilstein J. Org. Chem. 2021, 17, 1481–1489, doi:10.3762/bjoc.17.104

• give the tetralin product. Instead, we only isolated 30% yield of the difuranyl-substituted compound 15 as the major product. In addition, aldehydes 13e or 13f bearing a methyl group at the acetaldehyde side or the benzylic position of the alkene side were also suitable substrates for this cascade

• strategy: the 1,2,4-trisubsitituted tetralins 14ea and 14eb as well as the 2,4,4-trisubsitituted tetralins 14fa and 14fb were obtained in moderate to reasonable yields. The aldehyde 13g bearing a phenyl group at the benzylic position of the alkene side was also tried. Under the standard conditions, the

Fritsch–Buttenberg–Wiechell rearrangement of magnesium alkylidene carbenoids leading to the formation of alkynes

• Tsutomu Kimura,
• Koto Sekiguchi,
• Akane Ando and
• Aki Imafuji

Beilstein J. Org. Chem. 2021, 17, 1352–1359, doi:10.3762/bjoc.17.94

• reactive intermediates in which both magnesium and chlorine atoms are attached to an alkene carbon atom (Scheme 2a) [10]. Magnesium alkylidene carbenoids 3 can be generated from isopropylmagnesium chloride and 1-chlorovinyl p-tolyl sulfoxides 2, which are prepared from carbonyl compounds 1 and chloromethyl

• )magnesium chlorides, CH2=CXMgCl (X = F, Cl, and Br) << (1-chlorovinyl)lithium, CH2=CClLi. If the 1-heteroatom-substituted vinylmetal displays vinylidene characteristics, the FBW rearrangement occurs to give the alkyne. If not, the vinylmetal is simply protonated to give a heteroatom-substituted alkene. A

• reaction of (1-fluorovinyl)magnesium chloride with isopropylmagnesium chloride competed with the FBW rearrangement to give a mixture of alkyne 4a and alkene 10 in 69% and 13% yield, respectively (Table 1, entry 4, Scheme 4a, and Scheme 2c) [20]. Both the sulfoxide/magnesium exchange reaction and bromine

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

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• radical A. The subsequent hydrogen abstraction by radical A yields the key alkyl radical B. The addition of radical B or A to the alkene 7a following by an intramolecular cyclization provides the radical intermediates C or E, which are oxidized by the hole of CN-K via SET delivering the product 8a or

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

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

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

• Lewis acid (Scheme 53). Recently Xu et al. reported the homoallylic silyl alcohol 224 containing a multisubstituted (Z)-alkene reacting with an aldehyde in the presence of TMSI and InCl3 to afford 226 in high diastereoselectivity [96]. The authors assumed that the Prins cyclization proceeded through

• Alder’s chair-like transition state 227 in which the (Z)-alkene accounts for the trans-stereocontrol at the C3 position and equatorial iodide addition accounts for the cis-stereocontrol at the C4 position, as shown below in Scheme 54. The one-pot synthesis of tetrahydropyran by utilizing the Babier–Prins

• activation via DDQ oxidation, followed by nucleophilic attack of an unactivated olefin to obtain all-cis-trisubstituted Prins products with high stereochemical precision [111]. A single-electron transfer (SET) mechanism was proposed for the above transformation (Scheme 69). A SET from an arene or alkene to

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

• 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

• trifluoromethyl alkynylation product 84 with alkynyl sulfone 83, alkene 81, and Togni reagent 82 as substrates catalyzed by 2,4,6-trimethylpyridine (TMP). The EDA complex formed by electron donor TMP and electron acceptor Togni reagent 82 facilitated electron transfer, yielding trifluoromethyl radical to initiate

• triethylamine as additive at 20 °C and under 405 nm irradiation (Scheme 40). A standard residence time of 5 min was required for the full conversion via the EDA complex that formed by alkene and perfluoroalkyl iodide in flow, while longer residence times were requisite for less reactive alkenes. Moreover, the

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

• substituents at C3 and C4 of the formed 2-pyrrolidone ring predominated with moderate selectivity (Table 3, entries 2–7). The diastereomeric ratio is more or less independent of the nature of the amide substituent R1 or the substituent R4. Amide 9f with a methyl group at the internal position of the alkene

• alkene units furnished 4-isopropenylpyrrolidones 12g,k in very good yields as mixtures of inseparable diastereomers (Table 3, entries 7 and 11); no alkoxyamine-containing products were isolated. Lactam 12h with a defined hydroxy group configuration in the side chain at C3 of the lactam as well as

• (2R*,4S*)-9l as the major product (Scheme 8). The outcome of the thermal radical cyclizations of the dioxygenated amides 9 is dependent on the structure of the alkene unit, but the general trend is similar (Scheme 9). Amides with a terminal alkene unit furnished dioxygenated pyrrolidones 12a–f,h–j as

A new and efficient methodology for olefin epoxidation catalyzed by supported cobalt nanoparticles

• Lucía Rossi-Fernández,
• Viviana Dorn and
• Gabriel Radivoy

Beilstein J. Org. Chem. 2021, 17, 519–526, doi:10.3762/bjoc.17.46

• use of molecular oxygen as oxidant but require the use of high amounts (400–500% excess) of isobutyraldehyde as co-reductant. Therefore, there remains a need to develop and improve catalytic systems for alkene epoxidation by using low cost and easy to prepare supported cobalt nanoparticles as reusable

• very low conversion (pulegone, 22%) or did not react under the optimized conditions, even after 24 h of reaction time (methyl cinnamate, methyl acrylate, methyl methacrylate, isobutyl acrylate). For cycloalkenes (Table 2, entries 10–12) different oxidation patterns were observed depending on the alkene

• 2l coming from the α-oxidation of the starting alkene. It is known that the product selectivity in the oxidation of cyclohexene could be influenced by the catalyst and reaction conditions (solvent, temperature, catalyst loading, oxidant) [14]. Based on our experimental observations and those

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

• Beatrice Lansbergen,
• Catherine S. Meister and
• Michael C. McLeod

Beilstein J. Org. Chem. 2021, 17, 404–409, doi:10.3762/bjoc.17.36

• , with an HMBC cross-peak between the aryl ring and the alkene moiety proving most illuminating (see Supporting Information File 1). The geometry of the double bond was determined from a NOE interaction between the alkene proton and the ring hydrogen atoms. This molecule could not however be detected by

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• disubstituted alkene 13 in refluxing diglyme or triglyme at 190 °C (Scheme 7) [23]. The method has been widely used for the difluorocyclopropanation of allylic alcohol derivatives [24], steroids [25], and N-Boc-protected enamides [26]. Boron-substituted difluorocyclopropanes 16 can be also obtained from 12

• there was an opportunity to control the temperature, pressure, and to make the heat transfer more efficient [40]. The separate injection of a solution of the carbene precursor and of the alkene premixed with the activator did not lead to any improvement. Rullière et al. also tested this method on simple

• reaction of 54 with AlCl3 and an alkene at −20 °C (Scheme 22). The difluorocyclopropane 55 was obtained in 75% yield [63]. A bis(trifluoromethyl)zinc reagent was employed as the difluorocarbene source for the gem-difluorocyclopropanation of alkenes or alkynes via thermal decomposition [64]. The reagent was

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

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

• -metathesis reaction of 121 with alkene fragment (rac)-118 in the presence of Grubbs II (G-II) catalyst under optimized conditions produced (rac)-122 in 57% yield. After exhaustive experimentation, demethoxylation of (rac)-122 was achieved to produce (E,E,E)-aldehyde 123 predominantly in an 8:1 mixture of

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

• conditions to afford alkene (±)-39. Hydroboration of (±)-39 with the borane–THF complex followed by oxidation of the obtained intermediate led to the mixture of alcohols (±)-40 + (±)-41 with yields of 31% and 39%, respectively. The 1H NMR spectrum confirmed the structure and stereochemistry of alcohol (±)-41

• stereospecific semipinacol rearrangement in 78% yield over two steps. The resulting terminal alkene (−)-70 was submitted to Vacker's conditions to produce methyl ketone (−)-71 in 93% yield. The treatment of this ketone with potassium trimethylsilanolate induced a 1,5-Michael type reaction, via attack of tethered

• enone (−)-74, which was subjected to Luche reduction followed by removing the resulting alcohol under Barton–McCombie conditions, providing alkene (−)-75 in 55% yield from (−)-73. Finally, the acetal group of (+)-75 was hydrolyzed in the presence of catalytic Pd(MeCN)2Cl2. The intermediate ketone was

An atom-economical addition of methyl azaarenes with aromatic aldehydes via benzylic C(sp³)–H bond functionalization under solvent- and catalyst-free conditions

• Divya Rohini Yennamaneni,
• Vasu Amrutham,
• Krishna Sai Gajula,
• Rammurthy Banothu,
• Murali Boosa and
• Narender Nama

Beilstein J. Org. Chem. 2020, 16, 3093–3103, doi:10.3762/bjoc.16.259

• ) also reacted well and provided the alcohol 3e in 55% yield along with the alkene product 4e in 19% yield (Table 2, entry 5). Exceptionally, substrates with groups such as cyano, trifluoromethyl, and formyl were reacted and provided the respective dehydrated alkenylpyridine compounds 4i–k in 77%, 71

Silver-catalyzed synthesis of β-fluorovinylphosphonates by phosphonofluorination of aromatic alkynes

• Yajing Zhang,
• Qingshan Tian,
• Guozhu Zhang and
• Dayong Zhang

Beilstein J. Org. Chem. 2020, 16, 3086–3092, doi:10.3762/bjoc.16.258

• is the most rapid and convenient one (Scheme 1). Although studies on alkyne difunctionalization are ongoing [23], the successful attachment of a fluorine atom to the resulting alkene through transition metal catalysis remains a challenge. In particular, the phosphonofluorination of alkynes for the

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

• , France 10.3762/bjoc.16.256 Abstract The SF5Cl radical addition on unsaturated compounds was performed using an air-stable amine–borane complex as the radical initiator. This method showed to be complementary to the classic Et3B-mediated SF5Cl addition on alkenes and alkynes. A total of seven alkene and

• hydrogen reservoirs [40], as reducing agents in various transformations, including the reduction of aldehydes, amides and ketones, reductive aminations, alkene hydroboration, and carbon bond forming reaction [41][42], as well as various boronate and borinic acid precursors [43][44][45][46][47]. More

• recently, it has been shown that some of these common amine–borane complexes can also be used as radical initiators for atom transfer radical addition of alkyl halides to alkenes [48]. They were also used in the free-radical polymerization of alkene-containing monomers such as methyl methacrylate or

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

• Lee [24] independently in 2003. (Scheme 1C and Scheme 1D) In Krische’s synthesis, a stereospecific intramolecular phosphine-catalyzed [3 + 2] cycloaddition of 2-butynoate with electron-deficient alkene 29 afforded cycloadduct 31 in 88% yield as a single diastereomer [25] (Scheme 1C). Later, Lee`s

• trimethylsilyl ether. The electron-rich end of complex A attacks the carbon dioxide to give carboxylate B. Migration of the TMS group on carboxylate B generates the 1,3-dipole on C in the form of TMS carboxylate. An intermolecular [3 + 2] cycloaddition of C and alkene D (see Scheme 3B, inset) gives the

• fragmentation to afford alkene 72 in 61% yield. Marcfortine B (8) was synthesized from alkene 72 in seven steps. The enantioselective synthesis of marcfortine C (9) commenced with a catalytic asymmetric cyano-substituted TMM cycloaddition of oxindole 73 and TMM donor 75 with Pd(dba)2/74 as catalyst to give a

Ring-closing metathesis of prochiral oxaenediynes to racemic 4-alkenyl-2-alkynyl-3,6-dihydro-2H-pyrans

• Viola Kolaříková,
• Markéta Rybáčková,
• Martin Svoboda and
• Jaroslav Kvíčala

Beilstein J. Org. Chem. 2020, 16, 2757–2768, doi:10.3762/bjoc.16.226

• reactions of unsaturated compounds, e.g., alkene and enyne cross metathesis (CM [1] and EYCM [2][3][4]), alkene and enyne ring-closing metathesis (RCM and RCEYM) [5][6], ring-opening metathetic polymerization (ROMP) [7], etc., the CM and RCM are the most popular in organic synthesis [8]. Furthermore, the

• that a ruthenium-containing metathesis intermediate, formed by the alkene cross metathesis in the initiating step followed by a RCEYM, was deactivated by a subsequent reaction with the triple bond of the second enyne molecule. The results of the RCEYM of the ester-modified oxaenediyne 2e were

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• was another structural motif that could (i) mimic the extended geometry of an E-alkene, (ii) impart better solubility, and (iii) be more stable in the presence of UV light. Such a C=C surrogate might offer an improved lead compound for the development of drugs to treat Alzheimer’s disease

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

• process, an alkene reacts with a halogen cation to form a halonium ion, which immediately undergoes ring opening by fluoride to form a vicinal halofluoride (see Scheme 1). The overall result is an anti-addition of the XF moiety (X = Cl, Br, I) across the double bond. Since many nucleophilic fluorine

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

• reductively quenches the photocatalyst to form enaminyl radical 13•+. However, in this reaction 13•+ can then add to the alkene to give an alkyl radical 14•+, followed by hydrogen atom abstraction from the thiol, acting as a HAT catalyst, to give iminium ion intermediate 15. Hydrolysis of 15 generates the

• carboxylic acids 155 with alkenes 156. A low yielding benzylation reaction was required for determination of enantioselectivities and a large excess of alkene was required for the reaction. The reaction is proposed to proceed via hydrogen-bonded complex 157, that lowers the triplet energy of the carboxylic

• 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