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

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• ranged from 1:2 to 2:3 with a preference to 310a–315a regioisomers. An interesting approach to the synthesis of 1-indanones and 1-indenones is based on the hexadehydro-Diels–Alder (HDDA) reaction in which an alkyne reacts in the [4 + 2] cycloaddition with diyne and forms a reactive benzyne species as a

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• thorough literature search using Reaxys indicates that cyclohexanone has been made by [5 + 1] and [4 + 2] cycloaddition strategies thus validating the patterns of assembly shown in the third and fourth entries of Scheme 1 and the fourth entry of Scheme 2. The [5 + 1] literature examples involved insertion

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• chemoselectivity and excellent yield of 98% (Table 1, entry 10). With the optimal reaction conditions in hand, we examined the substrate scope of the enantioselective [4 + 2] cycloaddition between 5H-thiazol-4-ones 1 and N-itaconimides 2, catalyzed by DP-UAA V (Scheme 1). Firstly, with 1a as the model 5H-thiazol-4

• decreases the free energy of the second formal Mannich reaction, thus improving the reaction rate and chemoselectivity of the [4 + 2] cycloaddition. To extend the usefulness of this reaction, we demonstrate that the adduct can be efficiently reduced with borane. As shown in Scheme 2, 3a was readily reduced

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• , requiring a detailed examination of the kinetic versus thermodynamic effects. The nitroso hetero-Diels–Alder reaction involves the formation of the 3,6-dihydro-2H-1,2-oxazine scaffold 3 from nitroso dienophiles 1 and dienes 2 in a [4 + 2] cycloaddition reaction (Scheme 1). The first nitroso hetero-Diels

A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

• Mariano Goldberg,
• Denis Sartakov,
• Jan W. Bats,
• Michael Bolte and
• Michael W. Göbel

Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176

• the Michael products [19] which are the dominant products in polar solvents [25]. Previous mechanistic studies by Koerner and Rickborn [25] have collected strong arguments for a fast concerted [4 + 2]-cycloaddition of the deprotonated anthrone. Michael products were shown to be secondary products of a

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• ) or versipelostatin A (153) result from formal [4 + 2] cycloaddition reactions between exo-methylene groups and conjugated dienes. The required exo-methylene groups are installed by formal dehydration of 5-hydroxymethyltetronates. Leadlay et al. have confirmed that the respective reaction in

• analogous acetylation–elimination process was experimentally confirmed for quartromicin D1 (151) biosynthesis (Scheme 22) [145]. VstJ has been identified as a probable candidate for the enzyme-catalysed [4 + 2] cycloaddition in versipelostatin A (153) biosynthesis by heterologous expression, gene knockout

• the fact that four [4 + 2] cycloaddition events need to take place to assemble the four monomers into the highly symmetrical natural product [147]. Thiotetronates. Recently, Leadlay et al. presented their findings on the biosynthesis of thiotetronate antibiotics (Scheme 24) [148]. These small

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• , dehydropiperidine or piperidine is consistent with a [4 + 2] cycloaddition across two dehydrated serine residues [79][80]. Genetic disruption of tclM from the thiocillin pathway showed that TclM was responsible for this transformation [81], although the precise cyclisation mechanism (concerted or stepwise) could