Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors

• Emine Kayahan,
• Mathias Jacobs,
• Leen Braeken,
• Leen C.J. Thomassen,
• Simon Kuhn,
• Tom van Gerven and
• M. Enis Leblebici

Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202

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

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• not isolated but directly converted into the norbornadienyl trifluoromethyl ketone 3 (Scheme 1). The smooth [4 + 2] cycloaddition of 1a as compared to comparably harsh thermal conditions of other propyne ketiminium salts with an internal acetylenic bond reveals the activating influence of the CF3

• phenylacetylene and DMBD or isoprene [31]. On the other hand, the 1,1-diphenylpropargyl cation was found to react with 2,4-dimethyl-1,3-pentadiene to afford a product derived from an initial [4 + 2] cycloaddition [32]. When the Diels–Alder reaction of 1a with DMBD was carried out at room temperature instead of 0

• yielding a dihydronaphthalene 16. Formally speaking, 15 results from a [2 + 2] cycloaddition and 16 from a [4 + 2] cycloaddition (Diels–Alder reaction). Under the reaction conditions, cyclobutene 15 undergoes a fast electrocyclic ring opening leading to a butadiene 17, which is finally transformed into 2

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

An overview on disulfide-catalyzed and -cocatalyzed photoreactions

• Yeersen Patehebieke

Beilstein J. Org. Chem. 2020, 16, 1418–1435, doi:10.3762/bjoc.16.118

• method is also applicable for the synthesis of a wide variety of cyclopentane derivatives [12]. In 2017, Huang and co-workers reported a [4 + 2] cycloaddition reaction promoted by blue LED light, using aromatic olefins as the precursor, an acridinium photoredox catalyst (Mes–Acr–Ph+BF4−), and disulfide

• as the HAT cocatalyst, to generate the tetralin skeleton, which is widely seen in drugs and pesticide synthesis (Scheme 5) [13]. Diphenyl disulfide played an important role in the [4 + 2] cycloaddition process. Without diphenyl disulfide, only the product of the [2 + 2] cycloaddition was observed

• nonpolar solvent, PhSSPh accelerates the [4 + 2] cycloaddition of the radical cation 19, but the electron-relay catalyst promotes the [2 + 2] cycloaddition. The radical cation 19 can undergo two different types of cyclizations, subject to the relative reactivity of its radical and cation center. The α

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

• (Scheme 26) [61][67][68]. In this section, both reactions are presented and discussed. Singlet oxygen in pericyclic reactions Many important organic transformations can be performed by singlet oxygen including ene, [2 + 2] and [4 + 2] cycloaddition reactions for the formation of hydroperoxides, dioxetanes

• concerted) are still ongoing. The generally accepted mechanisms for these reactions are shown in Scheme 27, and propose a stepwise mechanism for ene and [2 + 2] cycloaddition, and a concerted mechanism for [4 + 2] cycloaddition [67]. In this part of the review, we decided to highlight the historically

Synthesis of acremines A, B and F and studies on the bisacremines

• Nils Winter and
• Dirk Trauner

Beilstein J. Org. Chem. 2019, 15, 2271–2276, doi:10.3762/bjoc.15.219

• be derived from two acremine F (5) units by a formal [4 + 2] cycloaddition followed by condensation and oxidation. Given the diversity and structural beauty of this class of natural products, it is not surprising that the acremine family has attracted the attention of the synthetic community [6][7][8

• both secondary allylic alcohols and afforded 2 in good overall yield (Scheme 3). Bisacremine E (7) was proposed to be formed in nature via [4 + 2] cycloaddition involving two acremine F (5) units [4]. Although dimerization of 5 through a Diels–Alder cycloaddition is not electronically favorable, we

An overview of the cycloaddition chemistry of fulvenes and emerging applications

• Ellen Swan,
• Kirsten Platts and
• Anton Blencowe

Beilstein J. Org. Chem. 2019, 15, 2113–2132, doi:10.3762/bjoc.15.209

• ] cycloadditions. For the former, the reaction of an aminodiene with a triafulvene initially resulted in the formation of a [2 + 2] cycloadduct, and an energetically strained 4-membered ring inevitably undergoes subsequent ring-opening (Scheme 13a) [10]. During the [4 + 2] cycloaddition, the triafulvene could only

• the yield of the Diels–Alder adduct [227]. Of particular interest is the reaction between 6-aminofulvenes and maleic anhydride. As previously reported, a fulvene reacting with maleimides (including maleic anhydride) generally results in a [4 + 2] cycloaddition (Scheme 14, reaction pathway (i)) [55][96

• derivative [22][27]. Reaction scheme for (a) [2 + 2] cycloaddition of 1,2-diphenylmethylenecyclopropene and 1-diethylamino-1,3-butadiene and (b) [4 + 2] cycloaddition of an in situ-generated triafulvene with cyclopentadiene. Diels–Alder cycloaddition of pentafulvenes derivatives participating as dienes with

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• stepwise Pd(II)-catalyzed cascade process or a [4 + 2] cycloaddition reaction, both providing the cis stereochemistry at C-2 and C-3. When the reaction was carried out with the epimer of substrate 33 (having the 5β-hydroxy group), the cis stereochemistry was also achieved at the newly formed C-2 and C-3

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• be isolated. Finally, cyclopropyl ketone 91 would first rearrange by copper catalysis and the so-obtained furane derivative 96 would add to the carbocation in 95, followed by Friedel–Crafts cyclization, thus generating the polycyclic isoindolinones 92 in a formal hetero [4 + 2] cycloaddition process

Catalytic asymmetric oxo-Diels–Alder reactions with chiral atropisomeric biphenyl diols

• Chi-Tung Yeung,
• Wesley Ting Kwok Chan,
• Wai-Sum Lo,
• Ga-Lai Law and
• Wing-Tak Wong

Beilstein J. Org. Chem. 2019, 15, 955–962, doi:10.3762/bjoc.15.92

• stereogenic centers in a one-step [4 + 2] cycloaddition or cyclization reaction [6][7][8] and it has become hugely popular in preparing vital intermediates for the syntheses of key structural subunits of natural products with biological activities (e.g., carbohydrates, antibiotics, toxins etc.) [9][10

Mechanistic studies of an L-proline-catalyzed pyridazine formation involving a Diels–Alder reaction with inverse electron demand

• Anne Schnell,
• J. Alexander Willms,
• S. Nozinovic and
• Marianne Engeser

Beilstein J. Org. Chem. 2019, 15, 30–43, doi:10.3762/bjoc.15.3

• formation of the enamine I seems plausible. It is an electron-rich dienophile which could undergo a [4 + 2] cycloaddition with the electron-poor aryl-substituted tetrazine 2 in a Diels–Alder reaction with inverse electron demand. The bicyclic Diels–Alder intermediate II then might undergo a retro-Diels

• contrast to the other two intermediates might indicate that the [4 + 2] cycloaddition between enamine intermediate I3 and tetrazine substrate 2 in R3 does not proceed as easily as for the untagged reaction R1 discussed above. This difference in the kinetic behavior might be due to the higher steric

• hindrance for the [4 + 2] cycloaddition with the charge-tagged enamine intermediate I3 in comparison to the untagged enamine intermediate I1. Thus, the use of the charge-tagged catalyst was essential for the detection of the elusive, but mechanistically most interesting intermediate II3. However, this comes

Microfluidic light-driven synthesis of tetracyclic molecular architectures

• Javier Mateos,
• Nicholas Meneghini,
• Marcella Bonchio,
• Nadia Marino,
• Tommaso Carofiglio,
• Xavier Companyó and
• Luca Dell’Amico

Beilstein J. Org. Chem. 2018, 14, 2418–2424, doi:10.3762/bjoc.14.219

• synthetic method for the direct assembly of highly functionalized tetracyclic pharmacophoric cores. Coumarins and chromones undergo diastereoselective [4 + 2] cycloaddition reactions with light-generated photoenol intermediates. The reactions occur by aid of a microfluidic photoreactor (MFP) in high yield

• anticipated that the successful development of these photoreactions would generate valuable privileged scaffolds, namely, naphthochromenones 4 and benzoxanthenes 5, through a diastereoselective light-driven [4 + 2] cycloaddition reaction. Interestingly, the tetracyclic scaffolds 4 and 5 are embodied in

• optimal reaction conditions for the light-driven [4 + 2] cycloaddition were achieved within a 1000 μL MFP with a residence time set at 35 min forming product 4a in quantitative yield, complete diastereocontrol and a productivity of 0.104 mmol·h−1 (Table 1, entry 4). On the contrary, when the same reaction

First thia-Diels–Alder reactions of thiochalcones with 1,4-quinones

• Grzegorz Mlostoń,
• Katarzyna Urbaniak,
• Paweł Urbaniak,
• Anna Marko,
• Anthony Linden and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2018, 14, 1834–1839, doi:10.3762/bjoc.14.156

• cycloadducts could be expected, but the 1H NMR analysis of the crude products showed that only one product was present in each case and, therefore, the studied [4 + 2] cycloaddition reactions occurred with complete regioselectivity. Based on the assumption that the nucleophilic S-atom of the thiochalcone

Cobalt-catalyzed C–H cyanations: Insights into the reaction mechanism and the role of London dispersion

• Eric Detmar,
• Valentin Müller,
• Daniel Zell,
• Lutz Ackermann and
• Martin Breugst

Beilstein J. Org. Chem. 2018, 14, 1537–1545, doi:10.3762/bjoc.14.130

• chemical transformations. Presumably due to attractive dispersive interactions between two adamantyl groups in the transition state of a [4 + 2] cycloaddition of benzynes (Scheme 1), the seemingly sterically more hindered product is formed preferentially [8]. Similar to other noncovalent interactions [9

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• bicyclic intermediate via a concerted [3 + 2]-cycloaddition followed by its very fast decomposition (extrusion of CO2) via a retro-Diels–Alder [4 + 2]-cycloaddition. The almost spontaneous extrusion of CO2 is caused by an energetically favorable aromatization occurring in this step leading to the formation

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

• iodobiarenes to synthesize a new class of I(III) and I(V) reagents 17. These were applied for the hydroxylative dearomatization of phenolic derivatives 42 followed by the successive use of the hydroxylated products as dienes in [4 + 2] cycloaddition reactions [42]. This new reagent promoted oxygen transfer in

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

• Diels–Alder reaction. Ghosh’s group reported an exclusive peri-, regio-, and stereoselective cycloaddition reaction of 5H-benzo[7]annulen-5-one (Scheme 35) [137]. The intermolecular [4 + 2] cycloaddition of 2,3-benzotropone (12) with cyclopentadiene (202) in the presence of boron trifluoride occurred

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• adducts. Due to the important pharmacological activities of these reactive o-QM intermediates, special attention is paid to the biological activity of these compounds. Keywords: aminophenols; [4 + 2] cycloaddition; dienophile; Mannich reaction; ortho-quinone methide; Review Introduction The Mannich

• at 78 °C, [4 + 2] cycloaddition took place between the o-QM generated from the corresponding aminonaphthol as diene component and cyclic imines playing the role of heterodienophiles (Scheme 5). Fülöp and co-workers then extended their studies by applying both 2-aminoalkyl-1-naphthols and 1-aminoalkyl

• intermediate 3. Asymmetric syntheses of triarylmethanes starting from diarylmethylamines. Proposed mechanism for the formation of 2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans 32. Cycloadditions of isoflavonoid-derived o-QMs and various dienophiles. [4 + 2] Cycloaddition reactions between

Preparation and isolation of isobenzofuran

• Morten K. Peters and
• Rainer Herges

Beilstein J. Org. Chem. 2017, 13, 2659–2662, doi:10.3762/bjoc.13.263

• laboratory scale with high yields, from affordable, commercially available starting materials. Keywords: [4 + 2] cycloaddition; Diels–Alder; isobenzofuran; trapping reagent; Introduction Isobenzofurans have been described as the most reactive dienes for Diels–Alder reactions [1][2][3][4][5]. Their high

One-pot syntheses of blue-luminescent 4-aryl-1H-benzo[f]isoindole-1,3(2H)-diones by T3P^® activation of 3-arylpropiolic acids

• Melanie Denißen,
• Alexander Kraus,
• Guido J. Reiss and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2017, 13, 2340–2351, doi:10.3762/bjoc.13.231

• , sensing and display applications [41]. 4-Phenylnaphtho[2,3-c]furan-1,3-diones can well serve as reactive intermediates in multicomponent reactions, e.g., for synthesizing the corresponding imides. A particularly intriguing access to 4-phenylnaphtho[2,3-c]furan-1,3-diones is the intramolecular [4 + 2

• ]-cycloaddition of phenylpropiolic acid anhydrides. Usually, this synthesis requires harsh reaction conditions starting from phenylpropiolic acids [42][43]. However, employing bis(2-oxooxazolidin-3-yl)phosphinic chloride as an activating agent represents a suitable access [44]. Alternative approaches include the

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• substituents were formed. Polycyclic products 35 were prepared through a concerted [4 + 2]-cycloaddition of E-1a with thiophene-functionalized fulvenes 36 [42] (Scheme 12). These cycloadducts are reported to undergo reversible intramolecular photocyclization to give products of type 37. The formation of the

• observed by 1H NMR spectroscopy [8]. Similar systems were prepared on solid phase and used as a new molecular recognition system [44]. The [4 + 2]-cycloaddition reactions of E- and Z-1b with electron-rich 1,3-dienes have been studied extensively by Sustmann and collaborators. Thus, 1-methoxybuta-1,3-diene

• carried out [45][48][50][51]. A stepwise reaction has also been suggested for the formal [4 + 2]-cycloaddition of E- and Z-1b with ethyl prop-1-enyl ether leading to a mixture of the corresponding 3,4-dihydro-2H-pyran and cyclobutane derivatives in a non-stereospecific manner [31]. A mechanism with the

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

• -bromooxime 26 with lithium enolate 27 to give oxime 28 via the Michael addition to transient nitrosoalkene NSA6 [31]. Oxime adduct 28 existed predominantly in a cyclic 1,2-oxazine form (Scheme 11). Subsequent benzylation of oxime 28 and the thermal retro-[2 + 2]/[4 + 2]-cycloaddition cascade followed by

• oximes 67 and 68 can occur not only via an SEAr mechanism, but also through an alternative [4 + 2]-cycloaddition/elimination pathway (for cycloaddition chemistry of nitrosoalkenes see reviews and accounts: [6][7][8][9][10][57][58]). In the recent work by Palacios and co-workers, the reaction of

• suggest that the [4 + 2]-cycloaddition process (2) is thermodynamically favored for nitrosoalkenes bearing electron-donating group R, whereas the presence of an electron withdrawing group at the same position promotes the electrophilic substitution pathway (1). Pinho e Melo and co-workers developed a one

Synthesis of the heterocyclic core of the D-series GE2270

• Christophe Berini,
• Thibaut Martin,
• Pierrik Lassalas,
• Francis Marsais,
• Christine Baudequin and
• Christophe Hoarau

Beilstein J. Org. Chem. 2017, 13, 1407–1412, doi:10.3762/bjoc.13.137

• the D-series thiopeptides have been explored, (i) the late-stage construction of the pyridine core through [4 + 2] cycloaddition reaction flanked with the main difficulties to prepare the dienophile and alkene bearing the adequate thiazolyl moieties or (ii) the direct connection and construction of

• within five Hantzsch thiazole building steps [14]. Nicolaou and Moody reported then the synthesis of the heterocyclic core of GE2270 by using a late-stage [4 + 2] cycloaddition of a sophisticated bithiazolylazadiene with alkynylated thiazole [15][16]. As highly innovative strategy, Bach reported in 2005

• of thiopeptides GE2270 in which the macrocylization and heterocyclic core was simultaneously achieved through a late-stage Negishi cross-coupling [18][19]. Last year, Yamaguchi’s group proposed a novel elegant [4 + 2] cycloaddition Kondrat’eva reaction between a 2-alkenylated thiazole-4-carboxylate

Exploring endoperoxides as a new entry for the synthesis of branched azasugars

• Svenja Domeyer,
• Mark Bjerregaard,
• Henrik Johansson and
• Daniel Sejer Pedersen

Beilstein J. Org. Chem. 2017, 13, 644–647, doi:10.3762/bjoc.13.63

• . Results and Discussion We set out to synthesise two diene substrates for a photochemical [4 + 2]-cycloaddition with singlet oxygen to provide two different endoperoxides (Scheme 1, n = 1–2). Based on literature precedent Boc-protection was utilised for the amino group (Scheme 2) [13][14]. Moreover, the

• Herein, we report the development of a synthetic strategy using [4 + 2]-cycloaddition reactions to yield endoperoxides 18–23 that contain a protected primary amine. Such intermediates serve as useful new building blocks for organic synthesis. Preliminary exploration of the chemistry of these compounds

• endoperoxide synthesis. TBA-Cl = tetrabutylammonium chloride, NCS = N-chlorosuccinimide. Synthesis of endoperoxides 17–19 by [4 + 2]-cycloaddition of dienes 14–16 with singlet oxygen. The photochemical reactor was modified with a gas inlet fitted with a filter at the bottom of the reactor, and the original