The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition

• Xiu-Yu Chen,
• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 982–990, doi:10.3762/bjoc.19.73

• as one of the most valuable synthons to construct diverse carbocyclic and heterocyclic systems as well as many open-chain compounds [9][10][11][12][13][14][15]. In recent years, in situ generated Huisgen 1,4-dipoles were also widely employed to design highly efficient multicomponent and domino

• reactions [16][17][18][19][20][21][22][23][24][25]. Recently, much attention has been devoted to the development of new domino reactions containing reactive Huisgen 1,4-dipoles as key components for the assembly of many biologically important nitrogen-containing six-membered heterocyclic compounds [26][27

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• ) [65]. In 2019, Piersanti and co-workers reported an organocatalyzed enantioselective aza-Friedel–Crafts/lactonization domino reaction sequence as the key step in the course of synthesizing (+)- and (−)-fumimycin. (−)-Fumimycin was first isolated from Aspergillus fumisynnematus and exhibits

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• explain why at lower onium salt amount and shorter reaction times the diastereoselectivities are higher but at the expense of the overall yield. With the optimized reaction conditions in our hands, we next explored the scope of the domino reaction. Structurally diverse onium compounds 2 were tested to

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and β-ketosulfonamides and sulfones

• Ksenia Malkova,
• Andrey Bubyrev,
• Stanislav Kalinin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 800–807, doi:10.3762/bjoc.19.60

• quinolines (sulfonamides and sulfones) (Figure 2b). Herein, we report the successful implementation of this approach. Results and Discussion The Knoevenagel condensation/aza-Wittig reaction cascade was used for the preparation of 3-sulfonyl-substituted quinolines. The process proceeds in a domino fashion

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• . through a multicomponent reaction system [57]. The authors provided a series of substituted derivatives through Pd/Rh-catalysed domino coupling. The reaction proceeded via a Suzuki coupling, followed by an in situ Buchwald–Hartwig amination. The authors reported moderate to good yields in a series with

• -pot domino Pd-catalyzed Mizoroki–Heck–Buchwald–Hartwig synthesis of dibenzo[b,f]azepines. Dibenzo[b,f]thiapine and -oxepine synthesis via SNAr (thio)etherification, Wittig methylenation and Mizoroki–Heck reaction. A retrosynthetic pathway to dibenzo[b,f]oxepines via Ullmann coupling. Ullmann-type

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• , crop-protecting agents, or advanced materials. Their syntheses often involve numerous reaction steps requiring laborious isolation and intermediate product purification steps. An important strategy for improving syntheses’ effectiveness is the concept of domino reactions, cascade, or tandem reactions

• asymmetric conjugate addition. The magnesium enolates 56 then participated in a copper(II)-mediated intramolecular oxidative coupling to afford benzofused spirocyclic cycloalkanones 57 (Scheme 14) [45]. Our team became interested in domino reactions of metal enolates generated by Cu-catalyzed asymmetric

• been shown to impart high levels of enantioselectivity for these ketones [46]. We performed the conjugate addition for 2 h and then added imine 58 having a tosyl protecting group. The workup allowed the isolation of domino products 59 as a mixture of diastereomers with dr 3:2 and enantiomeric purities

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• -catalyzed domino reactions of strained bicyclic alkenes, including both homo- and heterobicyclic alkenes. These compounds are important synthons in organic synthesis, providing an important platform for the construction of biologically/medicinally significant compounds which bear multiple stereocenters. The

• shed light on future directions for further development in this field. Keywords: bicyclic alkenes; cascade; catalysis; domino; transition-metal-catalyzed; Introduction A well-orchestrated sequence of events – cascade, also known as domino, tandem, and sequential reactions, constitutes a fascinating

• branch of organic chemistry dedicated to the synthesis of highly functionalized products through sequential transformations in a single reaction. Classically, a domino reaction has been defined by Tietze as a reaction involving two or more bond-forming transformations that take place under the same

Identification and determination of the absolute configuration of amorph-4-en-10β-ol, a cadinol-type sesquiterpene from the scent glands of the African reed frog Hyperolius cinnamomeoventris

• Angelique Ladwig,
• Markus Kroll and
• Stefan Schulz

Beilstein J. Org. Chem. 2023, 19, 167–175, doi:10.3762/bjoc.19.16

• concept proved to be difficult to achieve, but by optimization of different parameters of this Domino reaction, the required enantiomerically almost pure ketones 9–11 were obtained (Table 1). The Mannich reaction worked best using diisopropylammonium trifluoroacetate as the catalyst [22]. The isolation of

• ), diisopropylamine (0.4 equiv), TFA (0.1 equiv), THF, reflux, 3 d, ii) maleic anhydride (1.2 equiv), reflux, 16 h; d) MeMgBr (3.0 equiv), THF, reflux, 4 h. Screening of different reaction conditions with the (S)-Jørgensen’s organocatalyst S-16 for the key Domino reaction, consecutive Mannich and intramolecular Diels

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• ]. In 2010, Echavarren and co-worker completed the formal total synthesis via a Au(I)-catalyzed cyclization (Scheme 2c) [13]. In 2018, Pabbaraja and co-workers disclosed the synthesis of macarpine by constructing ring C through the domino Michael addition/SNAr reaction of nitromethane to an ynone

Molecular diversity of the base-promoted reaction of phenacylmalononitriles with dialkyl but-2-ynedioates

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 991–998, doi:10.3762/bjoc.18.99

• at room temperature resulted in 3,3-dicyano-5-hydroxy-5-arylcyclopent-1-ene-1,2-dicarboxylates in high yields. More importantly, the DABCO-promoted domino reaction of two molecules of each phenacylmalononitrile and dialkyl but-2-ynedioate in acetonitrile at room temperature afforded unique

• -carboxamides with unprecedented rearrangement of the alkyl group [34] (reaction 4 in Scheme 1). Inspired by these novel reactions and in continuation of our aim to develop domino reactions of electron-deficient alkynes [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], we have investigated the

• final product 4. It is due to the in situ formation and ring-opening of 2-oxabicyclo[2.2.1]hept-5-ene, that only one diastereoisomer 4 with the aryl group and the remaining cyano group in cis-position was selectively formed in the domino reaction process. In order to shed light on the proposed reaction

Tri(n-butyl)phosphine-promoted domino reaction for the efficient construction of spiro[cyclohexane-1,3'-indolines] and spiro[indoline-3,2'-furan-3',3''-indolines]

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 669–679, doi:10.3762/bjoc.18.68

• . Additionally, the tri(n-butyl)phosphine-promoted domino annulation reaction of isatins and ethyl isatylidene cyanoacetates produced spiro[indoline-3,2'-furan-3',3''-indolines] in satisfactory yields. Keywords: isatin; spiro[cyclohexane-1,3'-indoline]; spiro[indoline-3,2'-furan-3',3''-indoline]; spirooxindole

• respect, we have also developed several domino reactions by employing tertiary phosphine addition to electron-deficient alkynes as key protocol for the construction of diverse polycyclic spirooxindoles [53][54][55][56][57][58][59]. In continuation of our aim to explore elegant domino reactions for spiro

• isatylidene malononitriles or 3-(ethoxycarbonylmethylene)oxindoles for the efficient construction of two kinds of spiro[cyclohexane-1,3'-indolines] in good yields and with good diastereoselectivity. Additionally, tri(n-butyl)phosphine promoted the domino reaction of isatins and ethyl isatylidene cyanoacetates

DDQ in mechanochemical C–N coupling reactions

• Shyamal Kanti Bera,
• Rosalin Bhanja and
• Prasenjit Mal

Beilstein J. Org. Chem. 2022, 18, 639–646, doi:10.3762/bjoc.18.64

• practice by applying the strategies like domino, cascade, or tandem [11][12][13]. These environmentally friendly approaches set forth the journey of facilitating sustainable systems by using mechanochemical methods to access small organic compounds [3]. Due to the high reduction potential of the quinone

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• gate finally generated a catalytic output due to the assembly of a rotating four-component catalyst. Moreover, the AND gate could reversibly be reset into truth table state (0,0). Like the nanorotors above, domino nanorotors with two exchanging rotational axes showed catalytic action that depended on

• ]. Since at a given time, only one of both HETPYP-bound pyridines in [Cu4(76)2]4+ can serve as axle, the rotor undergoes a domino rotation that was measured to occur at k298 = 142 kHz. For the heteromeric rotor [Cu2(53)(76)]2+, two orthogonal dynamic interactions are relevant, i.e., the weak Npy → ZnPor

• ZnPor units of 53. Now there are two motions possible that can only occur in a domino fashion. When the strong HETTAP complexation is intact, the exchange of the pyridine head of 76 between both ZnPor sites of 53 occurs at 64 kHz at rt. When the much stronger HETTAP complex dissociates, the much weaker

Tosylhydrazine-promoted self-conjugate reduction–Michael/aldol reaction of 3-phenacylideneoxindoles towards dispirocyclopentanebisoxindole derivatives

• Sayan Pramanik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 469–478, doi:10.3762/bjoc.18.49

• ][10][11][12][13][14]. Among the known synthetic methodologies, the domino cycloaddition reaction of benzimidazolium salts with two molecules of 2-(2-oxoindolin-3-ylidene)acetates provided as an important tool for the construction of dispirooxindoles [15]. In particular, most of the dispirooxindole

• several research groups. In 2013, Yan et al. reported the construction of dispirocyclopentanebisoxindoles from the base-catalyzed domino reaction between two molecules of 3-phenacylideneoxindoles by participation of different solvents [23]. In 2016, the same research group reported the synthesis of

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• , contributing significantly to the progress of the synthesis studies in aqueous medium. The Diels–Alder reaction using menadione (10) was also studied by Bendiabdellah and co-workers, who reported the intramolecular Diels–Alder domino reactions promoted by Lewis acids [110]. The reaction involving menadione (10

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• tolerates a variety of substituents in both 22 and 23. From a mechanistic point of view, the reaction proceeds through a domino azomethine ylide formation/allylation/Pictet–Spengler reaction sequence. Recently, An and Xiao and co-workers disclosed high-yielding syntheses of a wide range of indole-3,4-fused

Recent developments and trends in the iron- and cobalt-catalyzed Sonogashira reactions

• Surendran Amrutha,
• Sankaran Radhika and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 262–285, doi:10.3762/bjoc.18.31

• 30 mol % of dmeda as ligand in toluene at 135 °C for 72 h (Scheme 7). On the other hand, acetylenes with alkyl substitution showed lower reactivity. In addition, to increase the importance of iron catalysts as a versatile tool in organic synthesis, a novel iron-catalyzed domino Sonogashira coupling

• . Fe-catalyzed Sonogashira coupling between terminal alkynes and aryl iodides. Iron-catalyzed domino Sonogashira coupling and hydroalkoxylation. Sonogashira coupling of aryl halides and phenylacetylene in the presence of Fe(III) acetylacetonate as catalyst. Sonogashira coupling of aryl iodides and

Earth-abundant 3d transition metals on the rise in catalysis

• Nikolaos Kaplaneris and
• Lutz Ackermann

Beilstein J. Org. Chem. 2022, 18, 86–88, doi:10.3762/bjoc.18.8

• nickel-catalyzed C–H functionalization [10]. Iron complexes are typically cost-effective and nontoxic, and therefore, their use in domino processes represents an outstanding prospect for sustainable organic syntheses [11]. Directed C–H activations have been developed as increasingly amenable tools for

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

• Jiang-Song Zhai and
• Da-Ming Du

Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3

• . Results and Discussion To verify the feasibility of the reaction, the domino Michael addition/cyclization reaction of 2-isothiocyanato-1-indanone (1a) and barbiturate-based olefin 2a was used as a model reaction, which was carried out in dichloromethane (DCM) with 5 mol % quinine-derived squaramide C1 at

• room temperature. The results are summarized in Table 1. We were pleased to find that the domino Michael addition/cyclization reaction could complete in the presence of 5 mol % C1 at room temperature in 12 h providing the desired product 3aa in 55% yield with excellent stereoselectivity (>20:1 dr, 97

• % ee) (Table 1, entry 1). Due to the excellent stereoselectivity of the target product 3aa, the reaction conditions were further optimized to increase its yield. Subsequently, a number of organocatalysts (Figure 3) were evaluated for this domino process (Table 1, entries 2–8). From the experimental

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• substantial improvements in efficient synthesis because of domino reactions. These protocols are more atom-economic, produce less waste, and demand less time compared to a classical stepwise reaction. Although iron-catalyzed domino reactions require a mindset that differs from the more routine noble-metal

• , homogenous iron catalysis they bear the chance to enable coupling reactions that rival that of noble-metal-catalysis. This review provides an overview of iron-catalyzed domino coupling reactions of π-systems. The classifications and reactivity paradigms examined should assist readers and provide guidance for

• the design of novel domino reactions. Keywords: cascade; catalysis; coupling; earth-abundant; iron; Introduction Over the past couple decades, the use of transition-metal-catalyzed cross-coupling reactions have become a staple within the organic chemist’s arsenal of carbon–carbon and carbon

Me₃Al-mediated domino nucleophilic addition/intramolecular cyclisation of 2-(2-oxo-2-phenylethyl)benzonitriles with amines; a convenient approach for the synthesis of substituted 1-aminoisoquinolines

• Krishna M. S. Adusumalli,
• Lakshmi N. S. Konidena,
• Hima B. Gandham,
• Krishnaiah Kumari,
• Krishna R. Valluru,
• Satya K. R. Nidasanametla,
• Venkateswara R. Battula and
• Hari K. Namballa

Beilstein J. Org. Chem. 2021, 17, 2765–2772, doi:10.3762/bjoc.17.186

• achieved by treating 2-(2-oxo-2-phenylethyl)benzonitriles with amines in the presence of Me3Al. The reaction proceeds via a domino nucleophilic addition with subsequent intramolecular cyclisation. This method provides a wide variety of substituted 1-aminoisoquinolines with good functional group tolerance

• -phenylethyl)benzonitriles was also examined. Scheme 3 summarizes the scope of 2-(2-oxo-2-phenylethyl)benzonitriles (3b–e) towards the domino nucleophilic addition followed by an intramolecular cyclisation of 2-(2-oxo-2-phenylethyl)benzonitriles with amines under optimal reaction conditions. Accordingly, 2-(2

• to yield the product 5. Conclusion In summary, an efficient Me3Al-mediated domino nucleophilic addition with a subsequent intramolecular cyclisation on 2-(2-oxo-2-phenylethyl)benzonitriles with amines was developed allowing access to widely substituted 1-aminoisoquinolines. Furthermore, the synthetic

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• backbone. Expected 9-aminofluorene intermediates 5 were envisaged to undergo subsequent oxidation by the same oxidant to hopefully provide the fluorenones 3 in a domino reaction. Results and Discussion After comprehensive literature search for successful oxidations of benzylic C–N bonds we tested a variety

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• (quinidinethiourea + ᴅ-proline), instead of the expected domino Mannich/Michael product, the bridged tetrahydroisoquinoline product 25a was obtained in high yield (90%) and excellent dr (94:6) and ee value (99%) (Table 5). The controlled reactions using 23 and 24 as the catalyst gave the product in very poor yield

• values of up to 95% and very good yields (≈99%) in all cases (Table 11) [45]. Guo et al. synthesized a variety of benzoindolizidines (56) from α,β-unsaturated aminoketones 54 through intramolecular domino aza-Michael addition/alkylation reactions. The reactions were carried out in the presence of

Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels–Alder reaction

• Ren-Jie Fang,
• Chen Yan,
• Jing Sun,
• Ying Han and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2021, 17, 2425–2432, doi:10.3762/bjoc.17.159

• attractive strategy for the synthesis of carbazole derivatives [28][29][30][31][32][33][34][35][36][37][38][39][40]. In recent years, by using the one-pot domino synthetic strategy of in situ-generated 2-vinyl- or 3-vinylindolines and sequential Diels–Alder reaction with activated dienophiles, we have

• successfully developed several efficient synthetic protocols for diversely functionalized tetrahydrocarbazoles and the corresponding carbazole derivatives [41][42][43][44][45][46][47]. To further demonstrate the synthetic application of domino Diels–Alder reactions and in continuation of our aim to providing

• efficient domino reactions for the synthesis of biologically important carbazole derivatives [48][49][50][51][52][53], herein we wish to report the DDQ-mediated dehydrogenative Diels–Alder reaction of 3-(indol-3-yl)maleimides and benzoyl-substituted 3-ethylindoles with readily available chalcones for the

Synthesis of phenanthridines via a novel photochemically-mediated cyclization and application to the synthesis of triphaeridine

• Songeziwe Ntsimango,
• Kennedy J. Ngwira,
• Moira L. Bode and
• Charles B. de Koning

Beilstein J. Org. Chem. 2021, 17, 2340–2347, doi:10.3762/bjoc.17.152

• ], rhodium-mediated alkyne [2 + 2 + 2] cycloaddition reactions [3], and the palladium-catalysed aerobic domino Suzuki coupling/Michael addition reaction [4]. The most attractive and common strategies to phenanthridines rely on intramolecular cyclizations of various ortho-functionalized biaryl precursors